Surgical system and methods of use

ABSTRACT

A surgical system including an implantable medical device having a size and shape. The surgical device having a substrate and a coating that covers at least a portion of the substrate. The coating including collagen, glycerin and a hemostatic agent. The substrate including a first piece and a second piece that is joined with the first piece. The first piece and the second piece forming a pocket having a cavity and an opening that is in communication with the cavity. The device being pre-formed such that a size and shape of the cavity conforms to the size and shape of the implantable medical device.

TECHNICAL FIELD

The present disclosure generally relates to anchorage devices andmethods configured for anchoring an implantable medical device within abody, wherein the anchorage device comprises at least one hemostaticagent that is configured to elute over time.

BACKGROUND

Some known anchorage devices may be used to secure an implantablemedical device within a body of a patient. The anchorage device andimplantable medical device can be inserted into a desired locationwithin the body of the patient. The anchorage device can be used to helpanchor or support the implantable medical device to surrounding tissue.Some known anchorage devices are used to provide temporary support totissue during a healing process. For example, some known anchoragedevices can secure one portion of tissue to another portion of tissue.

Infection and bleeding are the most serious complications after surgery.The estimated increase in costs due to surgical site infections (SSIs)was $11,876 for SS's overall ($7003 for superficial and $25,721 for deepinfections). However, within the current $6 billion hemostat market,there are few products that can address this unmet need. It wouldtherefore be desirable to stop or reduce the flow of blood at a surgicalsite and/or speed up the blood clotting process while anchoring theimplantable medical device to tissue. This disclosure describes animprovement over these prior art technologies.

SUMMARY

New anchorage devices and methods are provided to help anchor or supportan implantable medical device to surrounding tissue. In one embodiment,in accordance with the principles of the present disclosure, a surgicalsystem comprises an implantable medical device having a size and shape.A surgical device comprises a substrate and a coating that covers atleast a portion of the substrate. The coating comprises collagen,glycerin and a hemostatic agent. The substrate comprises a first pieceand a second piece that is joined with the first piece. The first pieceand the second piece form a pocket having a cavity and an opening thatis in communication with the cavity. The device is pre-formed such thata size and shape of the cavity conforms to the size and shape of theimplantable medical device.

In one embodiment, in accordance with the principles of the presentdisclosure, a surgical system comprises a package including an apertureand an insert positioned within the aperture. An implantable medicaldevice has a size and shape. The implantable medical device is animplantable device such as pulse generator (IPG) or diagnostic device.Example of such devices include a pacemaker or acardioverter-defibrillator. A surgical device comprises a substrate anda coating that covers at least a portion of the substrate. The coatingcomprises collagen, glycerin and a hemostatic agent. The collagenincludes CPP collagen or CPX collagen. The substrate comprises a firstpiece and a second piece that is joined with the first piece. The firstpiece and the second piece form a pocket having a cavity and an openingthat is in communication with the cavity. The device is pre-formed suchthat a size and shape of the cavity conforms to the size and shape ofthe implantable medical device. The insert is positioned in the cavityto maintain the size and shape of the cavity.

In one embodiment, in accordance with the principles of the presentdisclosure, a surgical system comprises a package including an apertureand an insert positioned within the aperture. An implantable medicaldevice has a size and shape. The implantable medical device is apacemaker or a cardioverter-defibrillator. A surgical device comprises asubstrate and a coating that covers at least a portion of the substrate.The coating comprises collagen, glycerin and a hemostatic agent. Thecollagen includes CPP collagen or CPX collagen. The substrate comprisesa first piece and a second piece that is joined with the first piece.The first piece and the second piece form a pocket having a cavity andan opening that is in communication with the cavity. The device ispre-formed such that a size and shape of the cavity conforms to the sizeand shape of the implantable medical device. The implantable medicaldevice is positioned in the cavity. The insert is configured to bepositioned in the cavity to maintain the size and shape of the cavity.

In one embodiment, in accordance with the principles of the presentdisclosure, a method of manufacturing a surgical device comprises:providing a substrate having opposite first and second sides, the secondside having a first section and a second section; coupling a substrateto a fixture such that the first side faces the fixture; and depositinga gel onto the second side such that the gel coats the first sectionwithout coating the second section

In one embodiment, in accordance with the principles of the presentdisclosure, a method of manufacturing a surgical device comprises:providing a substrate having opposite first and second sides, the secondside having a first section and a second section, wherein the substrateis an absorbable antibacterial envelope; coupling a substrate to afixture such that the first side faces the fixture; and 3D printing agel onto the second side such that the gel coats the first sectionwithout coating the second section. Wherein the first section comprisesa plurality of first sections that are spaced apart from one another bythe second section. In some embodiments, the gel consists oftrans-4-(aminomethyl)cyclohexanecarboxylic acid (C₈H₁₅NO₂) suspended ina solution, the solution consisting of collagen, water and glycerol. Insome embodiments, the gel consists oftrans-4-(aminomethyl)cyclohexanecarboxylic acid (C8H15NO2) suspended ina solution, the solution consisting of an alignate, water and glycerol.

In one embodiment, in accordance with the principles of the presentdisclosure, a method of manufacturing a surgical device comprises:providing a substrate having opposite first and second sides, the secondside having a first section and a second section, wherein the substrateis an absorbable antibacterial envelope; coupling a substrate to afixture such that the first side faces the fixture; and depositing a gelonto the second side using a robot such that the gel coats the firstsection without coating the second section. Wherein the first sectioncomprises a plurality of first sections that are spaced apart from oneanother by the second section. Wherein the gel consists oftrans-4-(aminomethyl)cyclohexanecarboxylic acid (C₈H₁₅NO₂) suspended ina solution, the solution consisting of collagen, water and glycerol

In one embodiment, in accordance with the principles of the presentdisclosure, a method of manufacturing a surgical device comprises:providing a substrate having opposite first and second sides; coupling asubstrate to a plate such that the first side faces the plate; andspraying a coating onto the second side.

In one embodiment, in accordance with the principles of the presentdisclosure, a method of manufacturing a surgical device comprises:providing a plate; coupling a polyimide liner directly to a planarsurface of the plate; coupling a mesh substrate to the liner such that afirst side of the substrate faces the liner and an opposite second sideof the plate faces away from the liner; positioning a hold down featureover the substrate to prevent movement of the substrate relative to theplate; spraying a coating onto the second side such that the coatingfills interstitial spaces of the mesh without the coating passingthrough the first side, the coating comprising collagen, glycerin and ahemostatic agent; and cooling the plate.

In one embodiment, in accordance with the principles of the presentdisclosure, a method of manufacturing a surgical device comprises:providing a plate; coupling a polyimide liner directly to a curvedsurface of the plate; coupling a mesh substrate to the liner such that afirst side of the substrate faces the liner and an opposite second sideof the plate faces away from the liner; positioning a hold down featureover the substrate to prevent movement of the substrate relative to theplate; spraying a coating onto the second side such that the coatingfills interstitial spaces of the mesh without the coating passingthrough the first side, the coating comprising collagen, glycerin and ahemostatic agent; and cooling the plate.

In one embodiment, in accordance with the principles of the presentdisclosure, a package for a surgical implant comprises a body having aside wall including opposite top and bottom ends. The body comprises abottom wall coupled to the bottom end. The body includes a flangeextending outwardly from the top end. Inner surfaces of the walls definea cavity. The top end defines an opening that is in communication withthe cavity. An insert extends from the bottom wall such that the insertis positioned in the cavity. A lid is configured to be coupled to theflange such that the lid covers the opening.

In one embodiment, in accordance with the principles of the presentdisclosure, a surgical system comprises a package comprising a bodyhaving a side wall including opposite top and bottom ends. The bodycomprises a bottom wall coupled to the bottom end. Inner surfaces of thewalls define a first cavity. The top end defines a first opening that isin communication with the first cavity. An insert extends from thebottom wall such that the insert is positioned in the first cavity. Theinsert has a size and shape. A surgical device comprises a substratecomprising a first piece and a second piece that is joined with thefirst piece. The first piece and the second piece form a pocket having asecond cavity and a second opening that is in communication with thesecond cavity. The device is pre-formed such that a size and shape ofthe second cavity conforms to the size and shape of the insert.

In one embodiment, in accordance with the principles of the presentdisclosure, a surgical system comprises a package comprising a bodyhaving a side wall including opposite top and bottom ends. The bodycomprises a bottom wall coupled to the bottom end. Inner surfaces of thewalls define a first cavity. The top end defines a first opening that isin communication with the first cavity. An insert extends from thebottom wall such that the insert is positioned in the first cavity. Theinsert has a size and shape defined by opposite first and second sidewalls of the insert that each extend from a top wall of the insert to anopposite bottom wall of the insert. The top wall is convexly curved fromthe first side wall to the second side wall. The first side wall extendsparallel to the second side wall from the top wall to the bottom wall ofthe insert. The insert includes opposite front and back walls that eachextend from the top wall to the bottom wall of the insert and from thefirst side wall to the second side wall. The front wall extends parallelto the back wall from the top wall to the bottom wall of the insert. Asurgical device comprises a substrate comprising a first piece and asecond piece that is joined with the first piece. The first piece andthe second piece form a pocket having a second cavity and a secondopening that is in communication with the second cavity. The device ispre-formed such that a size and shape of the second cavity conforms tothe size and shape of the insert. The device comprises a coating thatcovers at least a portion of the substrate. The coating consists ofcollagen, glycerin and trans-4-(aminomethyl)cyclohexanecarboxylic acid(C₈H₁₅NO₂)

Additional features and advantages of various embodiments will be setforth in part in the description that follows, and in part will beapparent from the description, or may be learned by practice of variousembodiments. The objectives and other advantages of various embodimentswill be realized and attained by means of the elements and combinationsparticularly pointed out in the description and appended claims.

BRIEF DESCRIPTION OF THE DRAWINGS

The present disclosure will become more readily apparent from thespecific description accompanied by the following drawings, in which:

FIG. 1 is a plan view of components of a surgical system, in accordancewith the principles of the present disclosure;

FIG. 2 is a perspective view showing one embodiment of making oneembodiment of a component of the surgical system shown in FIG. 1, inaccordance with the principles of the present disclosure;

FIG. 3 is a perspective view of one embodiment of a component of thesurgical system shown in FIG. 1, in accordance with the principles ofthe present disclosure;

FIG. 4 is a perspective view of one embodiment of a component of thesurgical system shown in FIG. 1, in accordance with the principles ofthe present disclosure;

FIG. 5 is a perspective view of one embodiment of a component of thesurgical system shown in FIG. 1, in accordance with the principles ofthe present disclosure;

FIG. 6 is a perspective view showing one embodiment of making oneembodiment of a component of the surgical system shown in FIG. 1, inaccordance with the principles of the present disclosure;

FIG. 6A is a perspective view showing one embodiment of making oneembodiment of a component of the surgical system shown in FIG. 1, inaccordance with the principles of the present disclosure;

FIG. 6B is a perspective view showing one embodiment of making oneembodiment of a component of the surgical system shown in FIG. 1, inaccordance with the principles of the present disclosure;

FIG. 7 is a perspective view showing one embodiment of making oneembodiment of a component of the surgical system shown in FIG. 1, inaccordance with the principles of the present disclosure;

FIG. 8 is a perspective view showing one embodiment of making oneembodiment of a component of the surgical system shown in FIG. 1, inaccordance with the principles of the present disclosure;

FIG. 9 is a perspective view of one embodiment of a component of thesurgical system shown in FIG. 1, in accordance with the principles ofthe present disclosure;

FIG. 10 is a perspective view of one embodiment of a component of thesurgical system shown in FIG. 1, in accordance with the principles ofthe present disclosure;

FIG. 11 is a perspective view of one embodiment of a component of thesurgical system shown in FIG. 1 packaged within another component of thesurgical system shown in FIG. 1, in accordance with the principles ofthe present disclosure;

FIG. 12 is a perspective view showing one embodiment of making oneembodiment of a component of a surgical system in accordance with theprinciples of the present disclosure;

FIG. 13 is a perspective view of one embodiment of a component of thesurgical system shown in FIG. 12, in accordance with the principles ofthe present disclosure;

FIG. 14 is a perspective view of one embodiment of a component of thesurgical system shown in FIG. 12, in accordance with the principles ofthe present disclosure;

FIG. 15 is a perspective view of one embodiment of a component of thesurgical system shown in FIG. 12, in accordance with the principles ofthe present disclosure, taken at detail A in FIG. 14;

FIG. 16 is a perspective view of one embodiment of a component of thesurgical system shown in FIG. 12, in accordance with the principles ofthe present disclosure;

FIG. 17 is a perspective view of one embodiment of a component of thesurgical system shown in FIG. 12, in accordance with the principles ofthe present disclosure;

FIG. 18 is a perspective view of one embodiment of a component of thesurgical system shown in FIG. 12;

FIG. 19 is a plan view of components and anatomy used in conjunctionwith the surgical system shown in FIG. 12;

FIG. 20 is a plan view of components and anatomy used in conjunctionwith the surgical system shown in FIG. 12; and

FIG. 21 is a plan view of components and anatomy used in conjunctionwith the surgical system shown in FIG. 12.

DETAILED DESCRIPTION

For the purposes of this specification and appended claims, unlessotherwise indicated, all numbers expressing quantities of ingredients,percentages or proportions of materials, and other numerical values usedin the specification and claims, are to be understood as being modifiedin all instances by the term “about.” Accordingly, unless indicated tothe contrary, the numerical parameters set forth in the followingspecification and attached claims are approximations that may varydepending upon the desired properties sought to be obtained by thepresent invention. At the very least, and not as an attempt to limit theapplication of the doctrine of equivalents to the scope of the claims,each numerical parameter should at least be construed in light of thenumber of reported significant digits and by applying ordinary roundingtechniques.

Notwithstanding the numerical ranges and parameters set forth herein,the broad scope of the invention are approximations, the numericalvalues set forth in the specific examples are reported as precisely aspossible. Any numerical value, however, inherently contains certainerrors necessarily resulting from the standard deviation found in theirrespective testing measurements. Moreover, all ranges disclosed hereinare to be understood to encompass any and all subranges subsumedtherein. For example, a range of “1 to 10” includes any and allsubranges between (and including) the minimum value of 1 and the maximumvalue of 10, that is, any and all subranges having a minimum value ofequal to or greater than 1 and a maximum value of equal to or less than10, e.g., 5.5 to 10.

Surgical site infections are increasing in frequency, severity and cost.Antibiotics are effective in eliminating short term infection atsurgical sites. However, their effectiveness in preventing biofilms ispoor, long term infections remain problematic and they often areeffective only on a subset of the pathogens and can cause bacterialresistance. This disclosure provides a fundamental shift in the thinkingof how to address infection by providing a new approach that can lead tobetter infection prevention outcomes, better overall healing andeliminate or minimize the use of antibiotics.

This disclosure is directed to a surgical system that includes one ormore active pharmaceutical ingredients together with one or morehemostatic agents in order to prevent or reduce bleeding via the one ormore hemostatic agents and provide another effect, such as, for example,an antimicrobial effect via the one or more hemostatic agents. In someembodiments, a coating that includes one or more active pharmaceuticalingredients together with one or more hemostatic agents is applied to asubstrate to coat at least a portion of the substrate to preventbacterial adhesion and form a defect-free conformal coating and/or ananostructured anti-bacterial surface upon implantation of thesubstrate. In some embodiments, the coating includes a polymer thatincludes the one or more active pharmaceutical ingredients and the oneor more hemostatic agents dispersed therein, as discussed herein. Insome embodiments, the coating does not include a polymer and issynthesized either all or in part from the one or more activepharmaceutical ingredients and the one or more hemostatic agents, asdiscussed herein.

In some embodiments, the one or more active pharmaceutical ingredientsand the one or more hemostatic agents are provided in a new polymericcoating that prevents bacterial adhesion and forms a defect-freeconformal coating and/or a nanostructured anti-bacterial surface. Insome embodiments, the coating is synthesized from antibacterialmaterials and have surface active groups such as carbohydrates inmonomer or polymer form that stimulate an immune response to eliminatethe bacteria or groups that attract growth factors for scar freehealing. It is envisioned that the coating that eliminates the long termuse of antibiotics. Eliminating the use of antibiotics can reduce therisk of developing antibiotics resistance bacterial.

In some embodiments, the one or more active pharmaceutical ingredientsand the one or more hemostatic agents are provided in a powder that canbe applied directly to a surgical site via a syringe or other deliverydevice, as discussed herein. The powder, that can both have hemostaticand antibacterial function, can be used with or without an anchoragedevice or other substrate that includes one or more activepharmaceutical ingredients together with one or more hemostatic agents.

This disclosure is directed to a surgical system that includes a new andeasy-to-use products, such as, for example novel devices device coatingsand powders that solve complications related to infection and/orbleeding by leveraging existing clinically proven TYRX antimicrobialtechnology (a tyrosine-derived polyarylate polymer that can be appliedto a substrate and is configured to release one or more agents, such as,for example, antimicrobial agents, over time as the substrate anchors animplantable medical device within a patient) and Medtronic MinimallyInvasive Technology Group (MITG) hemostatic technology containingoxidized cellulose substrate, (example product is Veriset). VERISET ismade of oxidized cellulose coated with multiple arm PEG and triglycine.PEG and triglycine are functionalized and can react with each other uponwet, forming a hydrogel for stopping the bleeding. In addition, theoxidized cellulose can trigger clotting and platelet aggregation toprovide hemostatic effect. The core technology in TYRX antimicrobialtechnology is the controlled drug release over extended period. Thecoating can be processed into a variety of form factors such asparticles, then paste and gel. These particles can be used to make aproduct in powder form, while paste and gel can be further made from thepowder. Paste and gel are preferred sometime as they are easily tocontrol for application, or in the case here, a liquid that gels whendeposited and cooled to a lower temperature. By mixing these particlesinto a hemostatic matrix, such as oxidized cellulose, it will createcombinational coatings and other products for reducing bleeding andinfection. Additionally, pain medications can be added easily such asbupivacaine.

In some embodiments, a TYRX antibacterial envelope is used to treatsurgical site infections by delivery of two antibiotics. VERISEThemostat, used to control bleeding is made from oxidized cellulose and aPEG compound. A powder can be made from the coating of the TYRX envelopeand oxidized cellulose in the VERISET. A power can also be made bygrounding both the TYRX mesh and VERISET product.

In some embodiments, an anchorage device is provided that includes asubstrate is in the form of an envelope. A coating coats at least aportion of the envelope, wherein the coating is made from drugs, suchas, for example, antibacterial drugs, that are dispersed throughout atyrosine polymer and oxidized cellulose.

Treatments for infection control and bleeding are available. Thisdisclosure is directed to a surgical system that provides a way to treatboth complications (infections and bleeding) simultaneously, bydelivering the hemostat and antibiotics together. In some embodiments,the surgical system includes a TYRX antibacterial envelope that is usedto treat surgical site infections by delivery of two antibiotics and aVERISET hemostat that is used to control bleeding. In some embodiments,the VERISET hemostat is made from oxidized cellulose and a PEG compound.In some embodiments, the envelope is processed into a first powder andthe VERISET hemostat is processed into a second powder. The first andsecond powders are combined. Other components are added to the combinedfirst and second powders to form a coating and/or other productsconfigured to simultaneously treat and/or prevent infection andbleeding.

In some embodiments, the surgical system has a hemostatic andantibacterial dual function, as discussed herein. In some embodiments,the surgical system includes components that are easy to deliver. Insome embodiments, the surgical system includes components that are FDAcleared. In some embodiments, the surgical system includes componentsthat have no known interaction between them. In some embodiments, thesurgical system is easy to manufacture. In some embodiments, thesurgical system includes a convenient delivery system. In someembodiments, the surgical system is readily adaptable to differentdrugs. In some embodiments, absorption time can be tuned depending uponapplication. In some embodiments, animal models can be used to testefficacy. In some embodiments, the surgical system will have a minimalimpact on surgery time.

In some embodiments, this disclosure is directed to a surgical systemthat includes coatings and/or other products that include powders of oneor more antibacterial drugs in tyrosine polymers. In some embodiments,coatings and/or other products include powders of one or moreantibacterial drugs in oxidized cellulose.

In some embodiments, a collagen and glycerol coating containing TXA isapplied to an TYRX envelope to raise its efficacy by preventingexcessive hemorrhaging in the pocket formed for the implanted devicesuch as a pacer or an cardioverter-defibrillator, etc. The TXA may alsobe applied to TYRX type patches that are cut to size for givenapplication and operation and are employed in operations where bleedingcontrol is desirable or necessary.

This disclosure is further directed to a method for depositing a novelcoating on an implant or other device to simultaneously treat and/orprevent infection and bleeding. In some embodiments, the method includesdepositing the coating on a substrate using a robotically controlled geldispensing system. In some embodiments, the method includes depositingrows or other shapes on a mesh, wherein the mesh can be backed orunbacked. In some embodiments, multiple tip printing is utilized toprovide multiple colors. In some embodiments, the method includesdepositing 3D shapes of the coating on a substrate. In some embodiments,the method includes leaving selected portion(s) of the substrateuncovered (not coated with the covering) to provide for better handlingin the operating room. In some embodiments, the gel coating that isdeposited on the substrate includes TXA suspended in a collagen, water,and glycerol solution.

This disclosure is further directed to a method for depositing a novelcoating on an implant or other device to simultaneously treat and/orprevent infection and bleeding. In some embodiments, the coating is acollagen and glycerol coating containing transexamic acid, wherein thecoating is applied to implants, such as, for example, surgical meshes.In some embodiments, the method includes depositing the coating on asubstrate such that the coating forms selected custom shapes, such as,for example, squares, rectangles, etc. where bleeding control isdesirable or necessary (soft tissue). In some embodiments, the methodincludes spraying droplets such that an uneven concentration of thecoating is formed as the coating impacts the substrate. In someembodiments, the method ensures even wetting. In some embodiments, themethod includes a plate, or shape, that contacts substrate in areaswhere the coating will be deposited. This reflow/wetting of thesubstrate (mesh) and the backing structure (plate, drum, half pipe,etc.) ensures even distribution and filling of interstitial spaces(porosity) of the substrate (mesh). In addition, the backing structureensures capture of all of the spray rather than letting some passthrough the openings in the substrate such as knit mesh.

In some embodiments, the disclosed surgical system includes packaging totransport an implant of the surgical system, such as, for example acoated mesh substrate from the manufacturer to a physician. Indeed, inthat mesh substrates tend to become more rigid after they are coated,the mesh substrates are typically immersed in saline, for example, inorder to wet the mesh substrate so that the mesh substrate becomespliable enough to insert an implantable medical device, such as, forexample, a pacemaker into the mesh substrate. However, the duration ofthe immersion has been proven difficult to predict and/or control. Assuch, in some embodiments, the disclosed surgical system includes adevice, such as, for example, a mesh substrate that is pre-formed tohave a selected shape while the mesh substrate is coated, wherein theselected shape matches the shape of the implantable medical device toallow the implantable medical device to be inserted into the meshsubstrate without wetting the mesh substrate or stretching/manipulatingthe mesh substrate to fit the implantable medical device within the meshsubstrate. The packaging of the disclosed surgical system is configuredto maintain the pre-formed shape of the mesh substrate as the meshsubstrate is transported from the manufacturer to a physician. In someembodiments, the packaging has a thermally formed shape. In someembodiments, the package includes a desiccant, a thermally sealed topflange and/or is sterilized.

Reference will now be made in detail to certain embodiments of theinvention, examples of which are illustrated in the accompanyingdrawings. While the invention will be described in conjunction with theillustrated embodiments, it will be understood that they are notintended to limit the invention to those embodiments. On the contrary,the invention is intended to cover all alternatives, modifications, andequivalents that may be included within the invention as defined by theappended claims.

This disclosure is directed to a surgical system 15. In someembodiments, system 15 includes one or more anchorage devices, such as,for example, an anchorage device 20. In some embodiments, the componentsof anchorage device 20 can be fabricated from biologically acceptablematerials suitable for medical applications, including metals, syntheticpolymers, allografts, xenografts, isografts, ceramics and bone materialand/or their composites, depending on the particular application and/orpreference of a medical practitioner. For example, the components ofanchorage device 20, individually or collectively, can be fabricatedfrom materials such as stainless steel alloys, commercially puretitanium, titanium alloys, Grade 5 titanium, super-elastic titaniumalloys, cobalt-chrome alloys, stainless steel alloys, superelasticmetallic alloys (e.g., Nitinol, super elasto-plastic metals, such as GUMMETAL® manufactured by Toyota Material Incorporated of Japan), ceramicsand composites thereof such as calcium phosphate (e.g., SKELITE™manufactured by Biologix Inc.), thermoplastics such aspolyaryletherketone (PAEK) including polyetheretherketone (PEEK),polyetherketoneketone (PEKK) and polyetherketone (PEK), carbon-PEEKcomposites, PEEK-BaSO₄ polymeric rubbers, polyethylene terephthalate(PET), fabric, silicone, polyurethane, silicone-polyurethane copolymers,polymeric rubbers, polyolefin rubbers, hydrogels, semi-rigid and rigidmaterials, elastomers, rubbers, thermoplastic elastomers, thermosetelastomers, elastomeric composites, rigid polymers includingpolyphenylene, polyamide, polyimide, polyetherimide, polyethylene,epoxy, tyrosine polyarylate, bone material including autograft,allograft, xenograft or transgenic cortical and/or corticocancellousbone, and tissue growth or differentiation factors, partially resorbablematerials, such as, for example, composites of metals and calcium-basedceramics, composites of PEEK and calcium based ceramics, composites ofPEEK with resorbable polymers, totally resorbable materials, such as,for example, calcium based ceramics such as calcium phosphate,tri-calcium phosphate (TCP), hydroxyapatite (HA)-TCP, calcium sulfate,or other resorbable polymers such as polylactide, polyglycolide,polytyrosine carbonate, polycaroplactone and their combinations.

Various components of anchorage device 20 may have material composites,including the above materials, to achieve various desiredcharacteristics such as strength, rigidity, elasticity, compliance,biomechanical performance, durability and radiolucency or imagingpreference. The components of anchorage device 20, individually orcollectively, may also be fabricated from a heterogeneous material suchas a combination of two or more of the above-described materials. Thecomponents of anchorage device 20 may be monolithically formed,integrally connected or include fastening elements and/or instruments,as described herein.

Anchorage device 20 includes a substrate, such as, for example,substrate 22. Substrate 22 is configured to be coupled to and/or appliedto a device, such as, for example, a medical device 25. In someembodiments, medical device 25 is an implantable medical device, asdiscussed herein. In some embodiments, medical device 25 is anon-implantable medical device, as discussed herein. In someembodiments, substrate 22 is configured to surround and/or enclose atleast a portion of medical device 25, as discussed herein. Substrate 22is configured to be secured to tissue to support one or more devices 25,such as grafts (e.g., abdominal aortic aneurysm grafts, etc.), stents,catheters (including arterial, intravenous, blood pressure, stent graft,etc.), valves (e.g., polymeric or carbon mechanical valves,), embolicprotection filters (including distal protection devices), vena cavafilters, aneurysm exclusion devices, artificial hearts, cardiac jackets,and heart assist devices (including left ventricle assist devices),implantable defibrillators, subcutaneous implantable defibrillators,implantable monitors, for example, implantable cardiac monitors,electrostimulation devices and leads (including pacemakers, leadadapters and lead connectors), implanted medical device power supplies,peripheral cardiovascular devices, atrial septal defect closures, leftatrial appendage filters, valve annuloplasty devices, mitral valverepair devices, vascular intervention devices, ventricular assist pumps,and vascular access devices (including parenteral feeding catheters,vascular access ports, central venous access catheters).

Implantable medical devices may also include, for example, surgicaldevices such as sutures of all types, anastomosis devices (includinganastomotic closures), suture anchors, hemostatic barriers, screws,plates, clips, vascular implants, tissue scaffolds, cerebro-spinal fluidshunts, shunts for hydrocephalus, drainage tubes, catheters includingthoracic cavity suction drainage catheters, abscess drainage catheters,biliary drainage products, and implantable pumps. Implantable medicaldevices may also include, for example, orthopedic devices such as jointimplants, acetabular cups, patellar buttons, bone repair/augmentationdevices, spinal devices (e.g., vertebral disks and the like), bone pins,cartilage repair devices, and artificial tendons. Implantable medicaldevices may also include, for example, dental devices such as dentalimplants and dental fracture repair devices. Implantable medical devicesmay also include, for example, drug delivery devices such as drugdelivery pumps, implanted drug infusion tubes, drug infusion catheters,and intravitreal drug delivery devices. Implantable medical devices mayalso include, for example, ophthalmic devices such as scleral bucklesand sponges, glaucoma drain shunts and intraocular lenses.

Implantable medical devices may also include, for example, urologicaldevices such as penile devices (e.g., impotence implants), sphincter,urethral, prostate, and bladder devices (e.g., incontinence devices,benign prostate hyperplasia management devices, prostate cancerimplants, etc.), urinary catheters including indwelling (“Foley”) andnon-indwelling urinary catheters, and renal devices. Implantable medicaldevices may also include, for example, synthetic prostheses such asbreast prostheses and artificial organs (e.g., pancreas, liver, lungs,heart, etc.). Implantable medical devices may also include, for example,respiratory devices including lung catheters. Implantable medicaldevices may also include, for example, neurological devices such asneurostimulators, neurological catheters, neurovascular ballooncatheters, neuro-aneurysm treatment coils, and neuropatches, splints,ear wicks, ear drainage tubes, tympanostomy vent tubes, otologicalstrips, laryngectomy tubes, esophageal tubes, esophageal stents,laryngeal stents, salivary bypass tubes, and tracheostomy tubes.Implantable medical devices may also include, for example, oncologicalimplants. Implantable medical devices may also include, for example,pain management implants.

In some embodiments, substrate 22 is configured to be coupled to and/orapplied to or to surround and/or enclose at least a portion of anon-implantable medical device, as discussed herein. Non-implantabledevices can include dialysis devices and associated tubing, catheters,membranes, and grafts; autotransfusion devices; vascular and surgicaldevices including atherectomy catheters, angiographic catheters,intraaortic balloon pumps, intracardiac suction devices, blood pumps,blood oxygenator devices (including tubing and membranes), bloodfilters, blood temperature monitors, hemoperfusion units, plasmapheresisunits, transition sheaths, dialators, intrauterine pressure devices,clot extraction catheters, percutaneous transluminal angioplastycatheters, electrophysiology catheters, breathing circuit connectors,stylets (vascular and non-vascular), coronary guide wires, peripheralguide wires; dialators (e.g., urinary, etc.); surgical instruments (e.g.scalpels and the like); endoscopic devices (such as endoscopic surgicaltissue extractors, esophageal stethoscopes); and general medical andmedically related devices including blood storage bags, umbilical tape,membranes, gloves, surgical drapes, wound dressings, wound managementdevices, needles, percutaneous closure devices, transducer protectors,pessary, uterine bleeding patches, PAP brushes, clamps (includingbulldog clamps), cannulae, cell culture devices, materials for in vitrodiagnostics, chromatographic support materials, infection controldevices, colostomy bag attachment devices, birth control devices;disposable temperature probes; and pledgets.

Substrate 22 can have a variety of different configurations, shapes andsizes. For example, substrate 22 can be provided with a size and shapeor other configuration that can provide the functionality of supportingand immobilizing the medical device 25 at a treatment site within apatient's body, while also improving the removability of anchoragedevice 20 after the treatment has been completed. In some embodiments,medical device 25 can be disposed within a pocket defined by substrate22 and anchorage device 20 can be implanted and secured to tissue at adesired treatment site within a body of a patient. As discussed herein,during implantation, scar tissue can form at the treatment site and/ortissue can become ingrown within substrate 22. After the treatment iscompleted, medical device 25 can remain in the patient as discussedbelow or can be removed from the patient leaving anchorage device 20implanted. To remove anchorage device 20, tissue that is ingrown withinsubstrate 22 can be cut or otherwise detached from substrate 22. In someembodiments, a portion of anchorage device 20 may not be removable fromthe tissue and will remain implanted within the patient.

Substrate 22 may be formed with one or more biocompatible materials,which may be synthetic or naturally occurring. In some embodiments, theone or more biocompatible materials include, for example, polypropylene,polyester, polytetrafluoroethylene, polyamides, silicones, polysulfones,metals, alloys, titanium, stainless steel, shape memory metals (e.g.Nitinol), and/or combinations thereof. In some embodiments, substrate 22is made at least in part from one or more hemostatic agents, such as,for example, collagen. In some embodiments, substrate 22 is madeentirely from a hemostatic agent, such as, for example, collagen. Insome embodiments, substrate 22 is free of any hemostatic agents suchthat any hemostatic of device 20 would be included in a coating thatcoats substrate 22, rather from substrate 22 itself.

In some embodiments, substrate 22 is configured to be implantedtemporarily within a body of a patient and/or is configured to beremoved (e.g., explanted) from the patient's body after a period oftime. In such embodiments, substrate 22 may include a non-biodegradablematerial and/or a non-bioresorbable material. For example, substrate 22may be made entirely from a non-biodegradable material and/or anon-bioresorbable material such that substrate 22 is made only from thenon-biodegradable material and/or non-bioresorbable material. In someembodiments, substrate 22 may include one or more non-biodegradableand/or a non-bioresorbable material and one or more biodegradable and/orresorbable material. In some embodiments, one side of substrate 22 mayinclude one or more non-biodegradable and/or a non-bioresorbablematerial and another side of substrate 22 can include one or morebiodegradable and/or resorbable material.

As used herein, the term “biodegradable” refers to, for example, amaterial that can be at least partially broken down or degraded by abodily fluid and discarded as waste from the body and/or a material thatcan be broken down or degraded by a living organism. Thus,“non-biodegradable” can refer to a material that cannot be broken downor degraded by a bodily fluid and/or cannot be broken down or degradedby a living organism. As used herein the term “resorbable” refers to,for example, a material that can be at least partially broken down ordegraded by a bodily fluid and assimilated within the body. Thus, a“non-resorbable” material as used herein can refer to, for example, amaterial that cannot be broken down or degraded by bodily fluid andassimilated within the body.

In some embodiments, the biocompatible biodegradable and/orbioresorbable material or materials may include polymeric and/ornon-polymeric materials, such as, for example, one or more poly(alpha-hydroxy acids), poly (lactide-co-glycolide) (PLGA), polylactide(PLA), poly(L-lactide), polyglycolide (PG), polyethylene glycol (PEG)conjugates of poly (alpha-hydroxy acids), polyorthoesters (POE),polyaspirins, polyphosphazenes, collagen, hydrolyzed collagen, gelatin,hydrolyzed gelatin, fractions of hydrolyzed gelatin, elastin, starch,pre-gelatinized starch, hyaluronic acid, chitosan, alginate, albumin,fibrin, vitamin E analogs, such as alpha tocopheryl acetate, d-alphatocopheryl succinate, D,L-lactide, or L-lactide, -caprolactone,dextrans, vi nylpyrrolidone, polyvinyl alcohol (PVA), PVA-g-PLGA,PEGT-PBT copolymer (polyactive), methacrylates, poly(N-isopropylacrylamide), PEO-PPO-PEO (pluronics), PEO-PPO-PAAcopolymers, PLGA-PEO-PLGA, PEG-PLG, PLA-PLGA, poloxamer 407,PEG-PLGA-PEG triblock copolymers, POE, SAIB (sucrose acetateisobutyrate), polydioxanone, methylmethacrylate (MMA), MMA andN-vinylpyyrolidone, polyamide, oxycellulose, copolymer of glycolic acidand trimethylene carbonate, polyesteramides, tyrosine polyarylates,polyetheretherketone, polymethylmethacrylate, silicone, hyaluronic acid,chitosan, or combinations thereof. In one embodiment, substrate 22comprises Glycoprene, which is sold by Poly-Med, Inc. As used herein,the term “glycoprene” or “Glycoprene” refers to Glycoprene® orGlycoprene Ile. Glycoprene® can refer to different variations of thematerial sold under the trade name Glycoprene®, such as, for example,Glycoprene® 6829, Glycoprene® 8609 and Glycoprene® 7027.

In some embodiments, the biocompatible non-biodegradable and/ornon-bioresorbable material or materials may include polymeric and/ornon-polymeric materials, such as, for example, polyurethane, polyester,polytetrafluoroethylene (PTFE),polyethylacrylate/polymethylmethacrylate, polylactide,polylactide-co-glycolide, polyamides, polydioxanone, polyvinyl chloride,polymeric or silicone rubber, collagen, thermoplastics, or combinationsthereof.

In some embodiments, substrate 22 is configured to be permanentlyimplanted within a body of a patient. In such embodiments, substrate 22may include a biodegradable material and/or a bioresorbable material.For example, substrate 22 may be made entirely from a biodegradablematerial and/or a bioresorbable material such that substrate 22 is madeonly from the biodegradable material and/or bioresorbable material.

In some embodiments, substrate 22 is provided in the form of a mesh. Insome embodiments, the mesh is web or fabric with a construction ofknitted, braided, woven or non-woven filaments or fibers that areinterlocked in such a way to create a fabric or a fabric-like materialthat includes a matrix of filaments that define multiple pores. That is,the space between adjacent filaments or fibers define pores of the mesh.Pores may be beneficial to allow tissue in-growth, for example. In someembodiments, apertures may be formed in the mesh by cutting thefilaments or fibers to decrease the areal density (e.g., surfacedensity) or mass of the mesh and/or further facilitate tissue in-growth.In some embodiments, the apertures that extend through the filaments orfibers are larger than pores defined by the filaments or fibers.

In some embodiments, substrate 22 is provided in the form of a thinwalled structure, such as, for example, a wafer, sheet or tissue. Insome embodiments, the thin walled structure does not include any poresor apertures, in contrast to the mesh discussed herein. In someembodiments, the thin walled structure includes pores or apertures thatare smaller than the pores or apertures of the mesh discussed herein. Insome embodiments, the thin walled structure has a thickness that is lessthan a thickness of the mesh discussed herein. In some embodiments, thethickness of the thin walled structure is between about 0.001 inches andabout 0.1 inches.

In some embodiments, anchorage device 20 includes an overlay, such as,for example, a coating 24 that is applied to substrate 22 such thatcoating 24 covers all or a portion of substrate 22. In some embodiments,coating 24 can be processed into a variety of form factors such asparticles, then paste and gel. The particles may be mixed into ahemostatic matrix that comprises oxidized cellulose, for example.

In some embodiments, coating 24 includes collagen, glycerol and TXA andis configured to be applied directly to substrate 24. In someembodiments, the coating comprises between about 0.1 wt % and about 10wt % collagen, between about 90 wt % and about 99 wt % water, betweenabout 0.1 wt % and about 3.0 wt % glycerol, between about 0.1 wt % andabout 5.0 wt % TXA and between about 0.1 wt % and about 8.0 wt % 1NNaOH. In some embodiments, the coating comprises between about 1.2 wt %and about 5.4 wt % collagen, between about 87.1 wt % and about 97.1 wt %water, between about 0.2 wt % and about 2.2 wt % glycerol, between about0.1 wt % and about 2.0 wt % TXA and between about 0.3 wt % and about 4.3wt % 1N NaOH. In some embodiments, the coating comprises about 3.4 wt %collagen, about 92.1 wt % water, about 1.2 wt % glycerol, about 0.9 wt %TXA and about 2.3 wt % 1N NaOH. In some embodiments, the coatingcomprises 3.4 wt % collagen, 92.1 wt % water, 1.2 wt % glycerol, 0.9 wt% TXA and 2.3 wt % 1N NaOH. In some embodiments, water may be reduced byup to a factor of 10.

In some embodiments, coating 24 can include one or more hemostatic agent(HA) and/or one or more active pharmaceutical ingredient (API). In someembodiments, coating 24 is free of any polymer such that the HA and theAPI are applied directly to substrate 22 in the form of a powder, forexample. In some embodiments, the HA and the API are dispersed within apolymer, such as, for example, one or more of the polymers discussedherein such that the polymer degrades to release the HA and the API uponimplantation of device 20. In some embodiments, substrate 22 isbiodegradable and/or bioresorbable and device 20 is configured to holdmedical device 25 therein such that substrate 22 does not begin todegrade until the polymer completely degrades such that device 20 canhold medical device 25 therein until all of the HA and the API arereleased from the polymer. In some embodiments, substrate 22 iscompletely biodegradable or bioresorbable. That all of substrate 22 isbiodegradable or bioresorbable. In some embodiments, substrate 22 iscompletely non-biodegradable and/or non-bioresorbable. That is noportion of substrate 22 is biodegradable or bioresorbable.

The HA can include one or more hemostatic agents, such as, for example,epinephrine, tranexamic acid, collagen, chitosan and oxidizedregenerated cellulose. In some embodiments, the collagen can includeacid soluble collagen, pepsin soluble collagen, gelatin, cross-linkablecollagen, fibrillar collagen. In some embodiments, the HA can includeone or more of Spongostan®, Surgifoam®, Avitene, thrombin and Ostene® inaddition to or in place of the hemostatic agents discussed above. Insome embodiments, the HA can include one or more of protamine,norepinephrine, desmopressin, lysine analogs, gelatin, polysaccharidespheres, mineral zeolite, bovine thrombin, pooled human thrombin,recombinant thrombin, gelatin and thrombin, collagen and thrombin,cyanacrylate, fibrin glue, polyethylene glycol, and glutaraldehyde inaddition to or in place of the hemostatic agents discussed above. Insome embodiments, the HA includes a mixture or combination of the HAsdiscussed herein. In some embodiments, the lysine analog is tranexamicacid and has the formula:

In some embodiments, the anchorage devices disclosed herein utilize oneor more pharmacologic hemostatic agent since pharmacologic hemostaticagents have been found to be desirable over mechanical hemostats for avariety of reasons. Ethnographic research has showed that physiciansdesire a hemostat that can provide an extended elution profile to reducebleeding events for up to 7 days post operatively. Furthermore, there isa possible effect on handling and/or allergic reactions if mechanicalhemostats, such as, for example, oxidized reduced cellulose or chitosanwere used.

In some embodiments, tranexamic acid is preferred for use as the HA.Tranexamic acid is a synthetic analog of the amino acid lysine with amolecular weight of 157 g/mol. Tranexamic acid is an antifibrinolyticagent that acts by binding to plasminogen and blocking the interactionof plasminogen with fibrin, therefore preventing the dissolution of afibrin clot. In the presence of a wound, fibrinolysis occurs naturallywhen a lysine residue such as tissue plasminogen activator (tPA), bindsto plasmin causing the clot to lyse (or break). Tranexamic acid blockstPA and keeps the clot from breaking, thus preventing unwanted bleeding.

Prior to a damaged endothelium, tPA is inhibited in the blood byplasminogen activator inhibitor/type 1 (PAI-1). Once damage occurs, thetPA is released slowly into the blood, activating fibrinolysis.Excessive fibrinolysis results in a condition called hvperfibrinolysis,which requires intervention such as fibrinogen, plasma, transfusion orantifibrinolytic therapy, such as tranexamic acid.

Tranexamic acid has been used for over 40 years to reduce bleedingcomplications. Tranexamic acid is most commonly given systemically atdoses of 10 mg/kg followed by infusion of 10 mg/kg/h. Since 2007,tranexamic acid has received widespread approval and clinical use as ahemostatic agent. Knowing that surgical trauma causes fibrinolysis inthe area of the surgical wound itself, topical antifibrinolytic therapyis becoming more common to obtain and maintain hemostasis. Clinicaltrials with topical tranexamic acid use exist for cardiac surgery, CIEDprocedures, orthopedic surgery, spinal surgery, dental extraction andepistaxis, and breast mammoplasty.

To evaluate the efficacy of tranexamic acid, a non-GLP acute porcinestudy was conducted. Doses of 1 mg to 200 mg of tranexamic acid wereused in an in vitro whole blood coagulation test, a hepatic biopsy test,and a subcutaneous ICD surgical procedure.

The in vitro whole blood coagulation test showed no activity fortranexamic acid up to 10 mg/ml. The maximum tranexamic acidconcentration, 200 mg/5 ml, was a slightly higher dose than that usedclinically in a CIED pocket if 50 cc is the assumed blood volume ofinterest. Coagulation time was doubled with this higher dose.

The hepatic biopsy test had a volume of 0.016 ml when the biopsy holewas filled with blood. The minimum tranexamic acid dose evaluated was2.5 mg, which is equivalent to 156 mg/ml. This concentration preventsblood from clotting quickly and these biopsies continued to bleed pastthe endpoint of 10 minutes. This phenomenon is likely due to themultiple bonding sites available to tranexamic acid in whole blood, andthe fact that a biopsy does not induce fibrinolysis.

The subcutaneous surgical site test was conducted with an elevated ACTusing heparin to induce hematoma. Surgical trauma similar to that of aCIEO implant was incurred in each pocket, but some subcutaneous pocketsincurred more trauma than others due to anatomical location. The primaryoutput monitored was accumulated blood as measured by pre-weighed gauze3-hours post-operatively. With only one animal, and two pockets pertreatment, the sample size was too low to show any significance betweenICD only, ICD+polymer, and ICD+polymer+tranexamic acid.

The non-GLP acute porcine study showed that in the dose range evaluated,tranexamic acid has a two-fold increase on clotting time and no effecton reducing bleeding on the hepatic biopsies. In the heparinized ICDpocket procedure, 3.5-22.8 grams of blood accumulated in a 3-hour periodof time regardless of treatment. It appears that subcutaneous pockets inan anticoagulated porcine model would be a translatable model forevaluating efficacy of tranexamic acid because it has a relevant volumeof accumulated blood and surgical trauma similar to that of a CIEDprocedure.

Based upon the non-GLP acute porcine study, tranexamic acidconcentrations of 3.00 mg/L to 30 mg/L are effective in preventingfibrinolysis. As such, in some embodiments, the HA is tranexamic acidand is provided in concentrations of about 3.00 mg/L to about 30 mg/L.However, it has been found that one tenth of the doses used in thenon-GLP acute porcine study can be effective in reversing fibrinolysis.As such, in some embodiments, the HA is tranexamic acid and is providedin concentrations of about 0.30 mg/L to about 3.0 mg/L for intravenousapplications. In some embodiments, tranexamic acid is provided inconcentrations of about 3.78 mg/L to about 30 mg/L for topicalapplications as well. However, in some embodiments, however, higherdoses of tranexamic acid are used for topical applications to accountfor tranexamic acid being widely distributed throughout theextracellular and intracellular compartments when given preoperatively.Indeed, it has been found that tranexamic acid reaches plasmaconcentrations in 5-15 minutes. As such, in some embodiments, tranexamicacid is provided in doses of about 1.5 mg to about 150 mg.

FIG. 5 shows bacterial adhesion, or the lack thereof. In particular,FIG. 5 shows the microscopic surface of the fixation device containing asurface active group such a carbohydrates in a monomer or polymer form.

In some embodiments, coating 24 may be applied to substrate 22 byspraying coating 24 onto substrate 22 (FIG. 2), coating all or a portionof substrate 22 with coating 24, or washing substrate 22 with coating24. In some embodiments, coating 24 is in the form of a gel when coating24 is applied to substrate 22. In particular, system 15 includes arobotically controlled gel dispensing system that applies coating 24 tosubstrate 22, as shown in FIG. 6. In some embodiments, substrate 22 isin the form of an envelope having an opening O into which a fixture orplate 28 of the robotically controlled gel dispensing system is insertedto position at least a portion of plate 28 within substrate 22 such thatplate 28 is positioned between opposite first and second sides of theenvelope. In some embodiments, plate 28 includes a single solid platethat is free of any openings or apertures that extend through athickness of plate 28. In some embodiments, plate 28 includes a plate 28a and a plate 28 b that is separated by a gap 30 and an aperture 32, asshown in FIG. 6. Coating 24 is dispensed by the robotically controlledgel dispensing system through a tip 34. In some embodiments, the fluidmay be heated to promote flow and wetting characteristics. The substrate(TYRX pouch) and fixture in FIG. 6 may be cooled as low as −10 to −15 Cto promote gelling and coating immobilization for subsequent handling.In some embodiments, the method includes coating the substrate with awarm coating material 40-60 C, allowing the coating material to gel onthe cooled fixture and moving to the coated substrate to a dryingoven/cabinet.

In some embodiments, the method described in the preceding paragraph isdifferent and necessary from other methods due to the amount of coatingthat needs to be deposited. In some situations, the device will bepre-wetted in a saline solution just prior to implant to make the deviceslippery and easier to slip onto a tissue pocket. This wetting dissolvessome of the coating and if the coating was thin, the relative amount ofcoating and drug content (TXA in this example) would be lost. If thecoating is thick with same amount of TXA, less TXA would be lost in thesame wetting process. The method described in the preceding paragraphhas key advantages over other methods. For example, the coating has anecessary high volume of collagen to prevent loss of the hemostaticagent during implant. It could be imagined that concentration of thehemostatic agent (TXA) was so high that only a thin coating is necessarythus spraying or dipping could be imagined. Such a thin coating (10×thinner) is too vulnerable to the procedure involving pre-wetting theEZGlide envelope. Furthermore, coating rates are high variable but ratesthat have been used to date include 0.05 cc/up to 0.65 cc/s.

In some embodiments, the robotically controlled gel dispensing systemapplies coating 24 to substrate 22 without any fixture or plate, suchas, for example, plate 28 being inserted into substrate 22.

In some embodiments, plate 28 provides several functions. For example,plate 28 acts a necessary backing plate that evenly distribute thecoating solution by wetting out concentrations (drops) that wouldotherwise form a lose mesh. Plate 28 immediately cools the coatingmaterial allowing the solution to gel in place. Plate 28 provides a wayto hold and flip the device to coat the other side. Plate 28 allows fortransportation of the coated fixture and a method fixture for subsequentdrying. Plate 28 may be coated with a non-stick coating such as NordicWare Platinum cooking surface coating.

In some embodiments, substrate 22 is in the form of a sheet and thesheet is positioned on top of plate 28. Coating 24 is dispensed ontosubstrate 22 through tip 34. In some embodiments, the roboticallycontrolled gel dispensing system applies coating 24 to sheet substrate22 without any fixture or plate, such as, for example, plate 28 beingapplied to sheet substrate 22. It is envisioned that substrates 22 ofvarious shapes and sizes can be coated using the robotically controlledgel dispensing system disclosed therein. That is, the use of therobotically controlled gel dispensing system for coating a substrate isnot limited by the size, shape or form of the substrate.

In some embodiments, the robotically controlled gel dispensing systemapplies coating 24 to substrate 22 in various configurations, whethersubstrate 22 in in the form of an envelope, a sheet, or otherwise. Insome embodiments, the robotically controlled gel dispensing systemapplies coating 24 to substrate 22 in rows. In some embodiments, therobotically controlled gel dispensing system applies coating 24 tosubstrate 22 in columns. In some embodiments, the robotically controlledgel dispensing system applies coating 24 to substrate 22 in selectedshapes, such as, for example, squares, rectangles, etc. In someembodiments, the robotically controlled gel dispensing system appliescoating 24 to substrate 22 in different colors. In some embodiments, therobotically controlled gel dispensing system applies coating 24 tosubstrate 22 in 3D shapes. In some embodiments, the roboticallycontrolled gel dispensing system applies coating 24 to substrate 22 suchthat at least a portion of substrate 22 is not covered with coating 24to facilitate handling of substrate 22 by a medical practitioner. Insome embodiments, rows or other shapes may be deposited on a mesh. Onemay also envision a multiple colors by introducing multiple tip“printing” allowing for use guidance markings, numbering, and even alogo. Rows and other shapes, omitted regions, etc. may also be possiblewith this method thus allowing for an area on the device that is notslippery from the coating and aids in handling by the surgeon.

In some embodiments, as shown in FIGS. 6A and 6B, system 15 is adaptedto facilitate robotic handling and fixation. Plate 28 may includefixturing datur, such as, for example, apertures 29 that are configuredfor disposal of extensions (not shown) of a clamp block 31. Inparticular, the extensions of clamp block 31 are each positioned withinone of apertures 29. Plate 28 is then sandwiched between clamp block 31and a cooling block assembly 33 in any manner known in the art. Coolingblock assembly 33 is configured to cool plate 28 via a refrigeratedsystem to a temperature between −10 degrees Celsius and −20 degreesCelsius. In some embodiments, cooling block assembly 33 is configured tocool plate 28 via a refrigerated system to −15 degrees Celsius. In someembodiments, the refrigerated system uses liquid nitrogen boil-off gasthat is applied directly to plate 28 and substrate 22. In someembodiments, clamp block 31 includes an engagement feature 35 that isconfigured for engagement with a component of system 15, such as, forexample, a component of the robotically controlled gel dispensing systemto apply a force to clamp block 31 to move clamp block 31 toward coolingblock assembly 33 to directly engage surfaces of clamp block 31 andcooling block assembly 33 with plate 28 to fix plate 28 relative toclamp block 31 and cooling block assembly 33. In some embodiments, thecomponent of the robotically controlled gel dispensing system thatapplies a force to clamp block 31 is an arm, such as, for example ahydraulic arm similar to that used with conventional drill presses. Insome embodiments, engagement feature 35 can be variously connected withthe component of the robotically controlled gel dispensing system thatapplies a force to clamp block 31, such as, for example, monolithic,integral connection, frictional engagement, threaded engagement, mutualgrooves, screws, adhesive, nails, barbs, raised elements, spikes, clips,snaps, friction fittings, compressive fittings, expanding rivets,staples, fixation plates, key/keyslot, tongue in groove, dovetail,magnetic connection and/or posts. In some embodiments, apertures 29 maybe variously shaped, such as, for example, oval, oblong, triangular,square, polygonal, irregular, uniform, non-uniform, offset, staggered,undulating, arcuate, variable and/or tapered.

In some embodiments, coating 24 is provided as a liquid or is sprayablesuch that coating 24 is sprayed onto substrate 22, as shown in FIGS. 7and 8. As coating 24 is sprayed onto substrate 22, droplets and unevenconcentration of coating 24 may form as coating 24 impacts substrate 22.In FIG. 7, the white plate is backing of the gray mesh such that thecoating liquid wets out the mesh and backing plate. This avoids theformation of droplets that are evident outside the white (PTFE in thecase) backing plate. In addition, such a coating eliminates the use ofsystem antibiotics—the coating eludes the drug content in the targetarea of need. A non-systemic approach lowers the risk of over usage andsubsequent resistant bacteria strains.

To ensure even wetting, substrate 22 is positioned on top of a plate 28such that plate 28 contacts substrate 22 in areas where coating 24 willbe deposited. Plate 28 allows for the even distribution of coating 24over all of substrate 22 or in selected sections of substrate 22 andfills the interstitial spaces of substrate 22. This method is thusparticularly useful when substrate 22 is in the form of a mesh. Plate 28ensures capture of all of coating 24 rather than letting some of coating24 pass through openings in substrate 22. In some embodiments, plate 28is a flat plate. However, it is envisioned that plate 28 can have otherforms, such as, for example, a drum or half pipe.

In some embodiments, for large substrates not the form of pouch that canbe slipped over a fixture such as described above, in order to ensuringthe single sheet stays in contact with the backing plate, it isconvenient to stretch/place it over a cylindrical shape or substantiallycylindrical. The “cylinder” may now be moved as one coordinate axiswhile a spray or fluid dispensing system traverses the orthogonal axis.In some embodiments, up to 10 times the concentration of the hemostaticagent (TXA) can be used thus allowing for coating with 10 times lessinitial volume of spray or deposition fluid. This comes with the abovementioned disadvantages when pre-wetting the device before implantingthe device.

In one embodiment, shown in FIG. 8, a sheet, such as, for example, apolyimide liner 38 is positioned between a plate 36 and substrate 22.Hold down features, such as, for example, rods 40 are coupled toopposite ends of substrate 22 such that substrate 22 is positionedbetween rods 40 and liner 38. That is, liner 38 directly engages a firstsurface of substrate 22 and rods 40 directly engage an opposite secondside of substrate 22 to couple substrate 22 to plate 36. System 15includes an actuator or other device that is configured to rotate plate36 while coating 24 is being deposited on substrate 22 or after coating24 has been deposited on substrate such that the rotation of plate 36evenly distributes coating 24 on substrate 22. As shown in FIG. 8, plate36 has an arcuate configuration that facilitates distribution of coating24 on substrate 22 as plate 36 rotates about a rotation axis RA. Thatis, as a spray head 42 sprays coating 24 onto substrate 22 and/or afterhead 42 spray coating 24 onto substrate 22, plate 36 rotates about axisRA to evenly distribute coating 24 along a surface of substrate. In someembodiments, plate 36 is cooled after coating 24 is deposited ontoplate. In some embodiments, the backing plate may be cooled via arefrigerated system to a temperature between −10 C to −20 C with −15 Cpreferred target temp. In some embodiments, cooling is achieve byapplying liquid nitrogen boil-off gas directly to both the fixture anddevice to be coated.

In some embodiments, coating 24 is selectively positioned on substrate22 such that coating 24 is targeted to a location of blood loss in apatient when the anchorage device is implanted within the patient. Inparticular, coating 24 is selectively positioned on substrate 22 suchthat coating 24 is targeted to a location to prevent or reduce bloodloss when the anchorage device is implanted within the patient. Forexample, once a location within the patient is identified where bloodloss is likely to occur or is occurring, a medical practitioner may useanchorage device 20 wherein coating 24 positioned on substrate 22 suchthat coating 24 will be positioned adjacent to the location where bloodloss is likely to occur or is occurring. As such, coating 24 will beable to effectively prevent, reduce or eliminate blood loss. In someembodiments, anchorage device 20 is delivered with coating 24 alreadyapplied to substrate 22. In some embodiments, anchorage device 22 iscustomizable. That is, the medical practitioner may be provided with ablank substrate, such as, for example, substrate 22 to which the medicalpractitioner can selectively apply coating 24. In particular, themedical practitioner can apply coating 24 to substrate 22 at a selectedarea of substrate 22 using one or more of the methods discussed hereinfor applying coating 24 to substrate 22, wherein the selected area(s) isan area of substrate 22 that will be positioned adjacent to the locationwithin the patient where blood loss is occurring or likely to occur whenanchorage device 20 is implanted within the patient.

In some embodiments, coating 24 is selectively positioned on substrate22 to define a pattern on substrate 22. In some embodiments, the patternincludes vertical and/or horizontal stripes that each include coating24. The stripes are spaced apart from one another by portions ofsubstrate 22 that do not include coating 24. In some embodiments, thestripes are formed by applying a material, such as, for example, maskingtape to substrate 22 in areas of substrate 22 where coating 24 is notdesired. Substrate 22 is then sprayed, coated, dipped in, or washed withcoating 24. The masking tape is then removed. It is envisioned that theprocess described herein about forming stripes may also be employed toapply coating 24 to substrate 22 to form any desired configuration. Forexample, the pattern can include a checkerboard pattern in which certainsquares of the pattern each include coating 24 and other squares of thepattern are free of coating 24. In some embodiments, the patternincludes shapes that are arranged in rows and columns.

In some embodiments, substrate 22 is formed at least in part fromhemostatic agent HA, as discussed herein. That is, substrate 22 is ahemostatic substrate that is made from hemostatic agent HA. In someembodiments, hemostatic substrate 22 is made only from hemostatic agentHA. In some embodiments, hemostatic agent HA does not include anycoating, such as, for example, coating 24. In some embodiments,hemostatic agent HA includes a coating, such as, for example, coating24. In some embodiments, coating 24 that is applied to hemostaticsubstrate 22 may include any of the coatings discussed herein. In someembodiments, coating 24 that is applied to hemostatic substrate 22includes the API.

Coating 24 is applied to hemostatic substrate 22 to such that anchoragedevice 20 delivers hemostatic agent HA in combination with the API. Insome embodiments, the API is applied directly to hemostatic substrate22. That is, the API is not applied to hemostatic substrate 22 in apolymer, such as, for example, a polymer that includes the API. In someembodiments, the API is applied to hemostatic substrate 22 via apolymer, such as, for example, one of the polymers discussed herein,wherein the polymer includes the API and releases the API as the polymerdegrades. In some embodiments, the API is applied to hemostaticsubstrate 22 via a polymer that includes also includes a hemostaticagent, such as, for example, one or more of the HAs. In someembodiments, the API is applied to hemostatic substrate 22 via a polymerthat does not include the HA, such as, for example, a polymer that isfree of the HA.

The API can include one or a combination of active pharmaceuticalingredients, such as, for example, anesthetics, antibiotics,anti-inflammatory agents, procoagulant agents, fibrosis-inhibitingagents, anti-scarring agents, antiseptics, leukotrieneinhibitors/antagonists, cell growth inhibitors and mixtures thereof. Insome embodiments, the API is an antibiotic. In some embodiments, theantibiotic is selected from the group consisting of rifampin andminocycline and mixtures thereof.

Examples of non-steroidal anti-inflammatories include, but are notlimited to, naproxen, ketoprofen, ibuprofen as well as diclofenac;celecoxib; sulindac; diflunisal; piroxicam; indomethacin; etodolac;meloxicam; r-flurbiprofen; mefenamic; nabumetone; tolmetin, and sodiumsalts of each of the foregoing; ketorolac bromethamine; ketorolacbromethamine tromethamine; choline magnesium trisalicylate; rofecoxib;valdecoxib; lumiracoxib; etoricoxib; aspirin; salicylic acid and itssodium salt; salicylate esters of alpha, beta, gamma-tocopherols andtocotrienols (and all their d, 1, and racemic isomers); and the methyl,ethyl, propyl, isopropyl, n-butyl, sec-butyl, t-butyl, esters ofacetylsalicylic acid.

Examples of anesthetics include, but are not limited to, licodaine,bupivacaine, and mepivacaine. Further examples of analgesics,anesthetics and narcotics include, but are not limited to acetaminophen,clonidine, benzodiazepine, the benzodiazepine antagonist flumazenil,lidocaine, tramadol, carbamazepine, meperidine, zaleplon, trimipraminemaleate, buprenorphine, nalbuphine, pentazocain, fentanyl, propoxyphene,hydromorphone, methadone, morphine, levorphanol, and hydrocodone. Localanesthetics have weak antibacterial properties and can play a dual rolein the prevention of acute pain and infection.

Examples of antibacterial agents or antimicrobials include, but are notlimited to, triclosan, chlorohexidine and other cationic biguanides,rifampin, minocycline (or other tetracycline derivatives), vancomycin,gentamycin; gendine; genlenol; genfoctol; clofoctol; cephalosporins andthe like. Further antibacterial agents or antimicrobials includeaztreonam; cefotetan and its disodium salt; loracarbef; cefoxitin andits sodium salt; cefazolin and its sodium salt; cefaclor; ceftibuten andits sodium salt; ceftizoxime; ceftizoxime sodium salt; cefoperazone andits sodium salt; cefuroxime and its sodium salt; cefuroxime axetil;cefprozil; ceftazidime; cefotaxime and its sodium salt; cefadroxil;ceftazidime and its sodium salt; cephalexin; hexachlorophene;cefamandole nafate; cefepime and its hydrochloride, sulfate, andphosphate salt; cefdinir and its sodium salt; ceftriaxone and its sodiumsalt; cefixime and its sodium salt; cetylpyridinium chloride; ofoxacin;linexolid; temafloxacin; fleroxacin; enoxacin; gemifloxacin;lomefloxacin; astreonam; tosufloxacin; clinafloxacin; cefpodoximeproxetil; chloroxylenol; methylene chloride, iodine and iodophores(povidone-iodine); nitrofurazone; meropenem and its sodium salt;imipenem and its sodium salt; cilastatin and its sodium salt;azithromycin; clarithromycin; dirithromycin; erythromycin andhydrochloride, sulfate, or phosphate salts ethylsuccinate, and stearateforms thereof, clindamycin; clindamycin hydrochloride, sulfate, orphosphate salt; lincomycin and hydrochloride, sulfate, or phosphate saltthereof, tobramycin and its hydrochloride, sulfate, or phosphate salt;streptomycin and its hydrochloride, sulfate, or phosphate salt;vancomycin and its hydrochloride, sulfate, or phosphate salt; neomycinand its hydrochloride, sulfate, or phosphate salt; acetyl sulfisoxazole;colistimethate and its sodium salt; quinupristin; dalfopristin;amoxicillin; ampicillin and its sodium salt; clavulanic acid and itssodium or potassium salt; penicillin G; penicillin G benzathine, orprocaine salt; penicillin G sodium or potassium salt; carbenicillin andits disodium or indanyl disodium salt; piperacillin and its sodium salt;α-terpineol; thymol; taurinamides; nitrofurantoin; silver-sulfadiazine;hexetidine; methenamine; aldehydes; azylic acid; silver; benzylperoxide; alcohols; carboxylic acids; salts; nafcillin; ticarcillin andits disodium salt; sulbactam and its sodium salt; methylisothiazolone,moxifloxacin; amifloxacin; pefloxacin; nystatin; carbepenems; lipoicacids and its derivatives; beta-lactams antibiotics; monobactams;aminoglycosides; microlides; lincosamides; glycopeptides; tetracyclines;chloramphenicol; quinolones; fucidines; sulfonamides; macrolides;ciprofloxacin; ofloxacin; levofloxacins; teicoplanin; mupirocin;norfloxacin; sparfloxacin; ketolides; polyenes; azoles; penicillins;echinocandines; nalidixic acid; rifamycins; oxalines; streptogramins;lipopeptides; gatifloxacin; trovafloxacin mesylate; alatrofloxacinmesylate; trimethoprims; sulfamethoxazole; demeclocycline and itshydrochloride, sulfate, or phosphate salt; doxycycline and itshydrochloride, sulfate, or phosphate salt; minocycline and itshydrochloride, sulfate, or phosphate salt; tetracycline and itshydrochloride, sulfate, or phosphate salt; oxytetracycline and itshydrochloride, sulfate, or phosphate salt; chlortetracycline and itshydrochloride, sulfate, or phosphate salt; metronidazole; dapsone;atovaquone; rifabutin; linezolide; polymyxin B and its hydrochloride,sulfate, or phosphate salt; sulfacetamide and its sodium salt; andclarithromycin (and combinations thereof). In some embodiments thepolymer may contain rifampin and another antimicrobial agent, such as,for example, an antimicrobial agent that is a tetracycline derivative.In some embodiments, the polymer contains a cephalosporin and anotherantimicrobial agent. In some embodiments, the polymer containscombinations including rifampin and minocycline, rifampin andgentamycin, and rifampin and minocycline.

When a mixture of two antibiotics is used, they generally present in aratio ranging from about 10:1 to about 1:10. In some embodiments, amixture of rifampin and minocycline are used. In those embodiments, aratio of rifampin to minocycline ranges from about 5:2 to about 2:5. Inother embodiments, the ratio of rifampin to minocycline is about 1:1.

Examples of antifungals include amphotericin B; pyrimethamine;flucytosine; caspofungin acetate; fluconazole; griseofulvin; terbinafineand its hydrochloride, sulfate, or phosphate salt; amorolfine; triazoles(Voriconazole); flutrimazole; cilofungin; LY303366 (echinocandines);pneumocandin; imidazoles; omoconazole; terconazole; fluconazole;amphotericin B, nystatin, natamycin, liposomal amptericin B, liposomalnystatins; griseofulvin; BF-796; MTCH 24; BTG-137586; RMP-7/AmphotericinB; pradimicins; benanomicin; ambisome; ABLC; ABCD; Nikkomycin Z;flucytosine; SCH 56592; ER30346; UK 9746; UK 9751; T 8581; LY121019;ketoconazole; micronazole; clotrimazole; econazole; ciclopirox;naftifine; and itraconazole.

In some embodiments, active pharmaceutical ingredient API includeskeflex, acyclovir, cephradine, malphalen, procaine, ephedrine,adriamycin, daunomycin, plumbagin, atropine, quinine, digoxin,quinidine, biologically active peptides, cephradine, cephalothin,cis-hydroxy-L-proline, melphalan, penicillin V, aspirin, nicotinic acid,chemodeoxycholic acid, chlorambucil, paclitaxel, sirolimus,cyclosporins, 5-fluorouracil and the like.

In some embodiments, the API includes one or more ingredients that actas angiogenensis inhibitors or inhibit cell growth such as epidermalgrowth factor, PDGF, VEGF, FGF (fibroblast growth factor) and the like.These ingredients include anti-growth factor antibodies(neutrophilin-1), growth factor receptor-specific inhibitors such asendostatin and thalidomide. Examples of useful proteins include cellgrowth inhibitors such as epidermal growth factor.

Examples of anti-inflammatory compounds include, but are not limited to,anecortive acetate; tetrahydrocortisol, 4,9(11)-pregnadien-17α,21-diol-3,20-dione and its -21-acetate salt; 111-epicortisol;17α-hydroxyprogesterone; tetrahydrocortexolone; cortisona; cortisoneacetate; hydrocortisone; hydrocortisone acetate; fludrocortisone;fludrocortisone acetate; fludrocortisone phosphate; prednisone;prednisolone; prednisolone sodium phosphate; methylprednisolone;methylprednisolone acetate; methylprednisolone, sodium succinate;triamcinolone; triamcinolone-16,21-diacetate; triamcinolone acetonideand its -21-acetate, -21-disodium phosphate, and -21-hemisuccinateforms; triamcinolone benetonide; triamcinolone hexacetonide;fluocinolone and fluocinolone acetate; dexamethasone and its-21-acetate, -21-(3,3-dimethylbutyrate), -21-phosphate disodium salt,-21-diethylaminoacetate, -21-isonicotinate, -21-dipropionate, and-21-palmitate forms; betamethasone and its -21-acetate, -21-adamantoate,-17-benzoate, -17,21-dipropionate, -17-valerate, and -21-phosphatedisodium salts; beclomethasone; beclomethasone dipropionate;diflorasone; diflorasone diacetate; mometasone furoate; andacetazolamide.

Examples of leukotriene inhibitors/antagonists include, but are notlimited to, leukotriene receptor antagonists such as acitazanolast,iralukast, montelukast, pranlukast, verlukast, zafirlukast, andzileuton.

In some embodiments, active pharmaceutical ingredient API includessodium 2-mercaptoethane sulfonate (“MESNA”). MESNA has been shown todiminish myofibroblast formation in animal studies of capsularcontracture with breast implants [Ajmal et al. (2003) Plast. Reconstr.Surg. 112:1455-1461] and may thus act as an anti-fibrosis agent.

Procoagulants include, but are not limited to, zeolites, thrombin, andcoagulation factor concentrates.

In some embodiments, the amount of the API that is applied to hemostaticsubstrate 22 via coating 24 or otherwise ranges between about 0.3 toabout 2.8 micrograms/cm². In other embodiments, the amount of the APIthat is applied to hemostatic substrate 22 via coating 24 or otherwiseranges between about 0.6 to about 1.4 micrograms/cm². In yet otherembodiments, the amount of the API that is applied to hemostaticsubstrate 22 via coating 24 or otherwise ranges between about 0.85 toabout 1.20 micrograms/cm². In yet further embodiments, the amount of theAPI that is applied to hemostatic substrate 22 via coating 24 orotherwise ranges between about 0.90 to about 1.10 micrograms/cm². In yetfurther embodiments, the amount of the API that is applied to hemostaticsubstrate 22 via coating 24 or otherwise ranges between about 50 toabout 150 micrograms/cm². In yet further embodiments, the amount of theAPI that is applied to hemostatic substrate 22 via coating 24 orotherwise ranges between about 62 to about 140 micrograms/cm². In yetfurther embodiments, 62 micrograms/cm² of the API is applied tohemostatic substrate 22 via coating 24 or otherwise. In yet furtherembodiments, 140 micrograms/cm² of the API is applied to hemostaticsubstrate 22 via coating 24 or otherwise. In some embodiments, a firstamount of the API is applied to hemostatic substrate 22 via coating 24and a second amount is applied to hemostatic substrate 22 via a powderthat is applied to substrate 22 after coating 24 is applied to substrate22. For example, anchorage device 22 may be delivered to a medicalpractitioner with coating 24 being pre-applied to substrate 22 andincluding a standard amount of the API. The medical practitioner maythen apply a powder, gel, slurry, solution, etc. of the API to thepre-applied coating 24 to add an additional amount of the API toanchorage device 20.

In some embodiments, the amount of the HA that is applied to hemostaticsubstrate 22 via coating 24 or otherwise ranges between about 0.3 toabout 2.8 micrograms/cm². In other embodiments, the amount of the HAthat is applied to hemostatic substrate 22 via coating 24 or otherwiseranges between about 0.6 to about 1.4 micrograms/cm². In yet otherembodiments, the amount of the HA that is applied to hemostaticsubstrate 22 via coating 24 or otherwise ranges between about 0.85 toabout 1.20 micrograms/cm². In yet further embodiments, the amount of theHA that is applied to hemostatic substrate 22 via coating 24 orotherwise ranges between about 0.90 to about 1.10 micrograms/cm². In yetfurther embodiments, the amount of the HA that is applied to hemostaticsubstrate 22 via coating 24 or otherwise ranges between about 50 toabout 150 micrograms/cm². In yet further embodiments, the amount of theHA that is applied to hemostatic substrate 22 via coating 24 orotherwise ranges between about 62 to about 140 micrograms/cm². In yetfurther embodiments, 62 micrograms/cm² of the HA is applied tohemostatic substrate 22 via coating 24 or otherwise. In yet furtherembodiments, 140 micrograms/cm² of the HA is applied to hemostaticsubstrate 22 via coating 24 or otherwise. In some embodiments, a firstamount of the HA is applied to hemostatic substrate 22 via coating 24and a second amount is applied to hemostatic substrate 22 via a powderthat is applied to substrate 22 after coating 24 is applied to substrate22. For example, anchorage device 22 may be delivered to a medicalpractitioner with coating 24 being pre-applied to substrate 22 andincluding a standard amount of the HA. The medical practitioner may thenapply a powder, gel, slurry, solution, etc. of the HA to the pre-appliedcoating 24 to add an additional amount of the HA to anchorage device 20.

In some embodiments, the amount of the HA and the API that is applied tohemostatic substrate 22 via coating 24 or otherwise ranges between about0.3 to about 2.8 micrograms/cm². In other embodiments, the amount of theHA and the API that is applied to hemostatic substrate 22 via coating 24or otherwise ranges between about 0.6 to about 1.4 micrograms/cm². Inyet other embodiments, the amount of the HA and the API that is appliedto hemostatic substrate 22 via coating 24 or otherwise ranges betweenabout 0.85 to about 1.20 micrograms/cm². In yet further embodiments, theamount of the HA and the API that is applied to hemostatic substrate 22via coating 24 or otherwise ranges between about 0.90 to about 1.10micrograms/cm². In yet further embodiments, the amount of the HA and theAPI that is applied to hemostatic substrate 22 via coating 24 orotherwise ranges between about 50 to about 150 micrograms/cm². In yetfurther embodiments, the amount of the HA and the API that is applied tohemostatic substrate 22 via coating 24 or otherwise ranges between about62 to about 140 micrograms/cm². In yet further embodiments, 62micrograms/cm² of the HA and the API is applied to hemostatic substrate22 via coating 24 or otherwise. In yet further embodiments, 140micrograms/cm² of the HA and the API is applied to hemostatic substrate22 via coating 24 or otherwise. In some embodiments, a first amount ofthe HA and the API is applied to hemostatic substrate 22 via coating 24and a second amount of the HA and the API is applied to hemostaticsubstrate 22 via a powder that is applied to substrate 22 after coating24 is applied to substrate 22. For example, anchorage device 22 may bedelivered to a medical practitioner with coating 24 being pre-applied tosubstrate 22 and including a standard amount of the HA and the API. Themedical practitioner may then apply a powder, gel, slurry, solution,etc. of the HA and the API to the pre-applied coating 24 to add anadditional amount of the HA and the API to anchorage device 20.

In other embodiments, the API includes rifampin and minocycline and theamount of each of rifampin and minocycline that is applied to hemostaticsubstrate 22 ranges between about 0.6 to about 1.4 micrograms/cm². Inyet other embodiments, the amount of each of rifampin and minocyclinethat is applied to hemostatic substrate 22 ranges between about 0.85 toabout 1.20 micrograms/cm². In yet further embodiments, the amount ofeach of rifampin and minocycline that is applied to hemostatic substrate22 ranges between about 0.90 to about 1.10 micrograms/cm². In someembodiments, a first amount of the rifampin and minocycline is appliedto hemostatic substrate 22 via coating 24 and a second amount of therifampin and minocycline is applied to hemostatic substrate 22 via apowder that is applied to substrate 22 after coating 24 is applied tosubstrate 22. For example, anchorage device 22 may be delivered to amedical practitioner with coating 24 being pre-applied to substrate 22and including a standard amount of the rifampin and minocycline. Themedical practitioner may then apply a powder, gel, slurry, solution,etc. of the rifampin and minocycline to the pre-applied coating 24 toadd an additional amount of the rifampin and minocycline to anchoragedevice 20.

The API may include one or more of the active pharmaceutical ingredientsdiscussed herein. The API may be incorporated into anchorage device 20by applying the API directly to hemostatic substrate 22 or by applyingthe API to hemostatic substrate 22 via a polymer, such as, for example,one or more of the polymers discussed herein. Doses of the APIsdiscussed herein are known and the amounts of any single API to includein anchorage device 20 can readily be surmised. Any pharmaceuticallyacceptable form of APIs discussed herein can be employed in anchoragedevice 20, e.g., the free base or a pharmaceutically acceptable salt orester thereof. Pharmaceutically acceptable salts, for instance, includesulfate, lactate, acetate, stearate, hydrochloride, tartrate, maleate,citrate, phosphate and the like.

In some embodiments, the API is applied directly to hemostatic substrate22, as discussed herein. In some embodiments, the API may be applied tohemostatic substrate 22 by spraying active pharmaceutical ingredient APIonto hemostatic substrate 22, coating all or a portion of hemostaticsubstrate 22 with the API, coating all or a portion of hemostaticsubstrate 22 with a material, such as, for example, one or more polymerthat includes the API, washing hemostatic substrate 22 with the API, orprinting the API on hemostatic substrate 22 with a printer, such as, forexample a 3D printer. In some embodiments, the API is a material thatforms hemostatic substrate 22. That is, hemostatic substrate 22 is madefrom the API and hemostatic agent HA is applied to hemostatic substrate22.

In some embodiments, anchorage device 20 includes hemostatic substrate22 wherein all or a portion of hemostatic substrate 22 is coated with afirst coating that includes one or more of the HAs and a second coatingthat includes one or more of the APIs, wherein the first coating is freeof any APIs other than the HAs and the second coating is free of anyHAs. In some embodiments, the first coating is applied directly tosubstrate 22 such that the first coating covers all or a portion ofsubstrate 22 and the second coating is applied over all or a portion ofthe first coating. In some embodiments, the second coating is applieddirectly to substrate 22 such that the second coating covers all or aportion of substrate 22 and the first coating is applied over all or aportion of the second coating. In some embodiments, anchorage device 20includes multiple layers of the first coating and/or the second coatingapplied to substrate 22.

In some embodiments, coating 24 is selectively positioned on hemostaticsubstrate 22 such that coating 24 is targeted to a location to treat atleast one condition when anchorage device 20 is implanted within thepatient. For example, once a location within the patient is identifiedthat has a certain condition, such as, for example, infection, scarringand/or infection, a medical practitioner may use anchorage device 20with coating 24 positioned on hemostatic substrate 22 such that coating24 will be positioned adjacent to the location having the condition whenanchorage device 20 is implanted within the patient. As such, coating 24will be able to effectively treat the condition by, for example,providing pain relief, inhibiting scarring or fibrosis and/or inhibitingbacterial growth.

The polymer discussed herein, such as, for example, the polymer ofcoating 24 that contains the HA and/or the API is selected from thegroup consisting of polylactic acid, polyglycolic acid, poly(L-lactide),poly(D,L-lactide)polyglycolic acid[polyglycolide],poly(L-lactide-co-D,L-lactide), poly(L-lactide-co-glycolide), poly(D,L-lactide-co-glycolide), poly(glycolide-co-trimethylene carbonate),poly(D,L-lactide-co-caprolactone), poly(glycolide-co-caprolactone),polyethylene oxide, polydioxanone, polypropylene fumarate, poly(ethylglutamate-co-glutamic acid), poly(tert-butyloxy-carbonylmethylglutamate), polycaprolactone, polycaprolactone co-butylacrylate,polyhydroxybutyrate, copolymers of polyhydroxybutyrate,poly(phosphazene), poly(phosphate ester), poly(amino acid),polydepsipeptides, maleic anhydride copolymers, polyiminocarbonates,poly[(97.5% dimethyl-trimethylene carbonate)-co-(2.5% trimethylenecarbonate)], poly(orthoesters), tyrosine-derived polyarylates,tyrosine-derived polycarbonates, tyrosine-derived polyiminocarbonates,tyrosine-derived polyphosphonates, polyethylene oxide, polyethyleneglycol, polyalkylene oxides, hydroxypropylmethylcellulose,polysaccharides such as hyaluronic acid, chitosan and regeneratecellulose. In some embodiments, the polymer may include combinations,blends or mixtures of the polymers discussed herein. In someembodiments, the polymer includes the HA and the API dispersed therein.In some embodiments, the HA and the API are uniformly dispersed in thepolymer.

In some embodiments, the polymer is a polyarylate. In some embodiments,the polymer is a tyrosine-derived polyarylate. In some embodiments, thetyrosine-derived polyarylate is p(DTE co X % DT succinate), where X isabout 10% to about 30%. In some embodiments, the tyrosine-derivedpolyarylate is p(DTE co X % DT succinate), where X ranges from about26.5% to about 28.5%. In some embodiments, the tyrosine-derivedpolyarylate is p(DTE co X % DT succinate), where X is about 27.5%. Insome embodiments, the polymer is P22-27.5 DT.

As used herein, DTE is the diphenol monomer desaminotyrosyl-tyrosineethyl ester; DTBn is the diphenol monomer desaminotyrosyl-tyrosinebenzyl ester; DT is the corresponding free acid form, namelydesaminotyrosyl-tyrosine. BTE is the diphenol monomer 4-hydroxy benzoicacid-tyrosyl ethyl ester; BT is the corresponding free acid form, namely4-hydroxy benzoic acid-tyrosine.

P22-XX is a polyarylate copolymer produced by condensation of DTE andDTBn with succinic acid followed by removal of benzyl group. P22-10,P22-15, P22-20, P22-XX, etc., represents copolymers different percentageof DT (i.e., 10, 15, 20 and % DT, etc.) In some embodiments, the polymeris produced by condensation of DTBn with succinic acid followed byremoval of benzyl group. This polymer is represented as P02-100.

In some embodiments, the polymer includes one or more polyarylates thatare copolymers of desaminotyrosyl-tyrosine (DT) and andesaminotyrosyl-tyrosyl ester (DT ester), wherein the copolymercomprises from about 0.001% DT to about 80% DT and the ester moiety canbe a branched or unbranched alkyl, alkylaryl, or alkylene ether grouphaving up to 18 carbon atoms, any group of which can, optionally have apolyalkylene oxide therein. Similarly, another group of polyarylates arethe same as the foregoing but the desaminotyrosyl moiety is replaced bya 4-hydroxybenzoyl moiety. In some embodiments, the DT or BT contentsinclude those copolymers with from about 1% to about 30%, from about 5%to about 30% from about 10 to about 30% DT or BT. In some embodiments,the diacids (used informing the polyarylates) include succinate,glutarate and glycolic acid.

In some embodiments, the polymer includes one or more biodegradable,resorbable polyarylates and polycarbonates. These polymers, include, butare not limited to, BTE glutarate, DTM glutarate, DT propylamideglutarate, DT glycineamide glutarate, BTE succinate, BTM succinate, BTEsuccinate PEG, BTM succinate PEG, DTM succinate PEG, DTM succinate, DTN-hydroxysuccinimide succinate, DT glucosamine succinate, DT glucosamineglutarate, DT PEG ester succinate, DT PEG amide succinate, DT PEG esterglutarate, DT PEG ester succinate, DTMB P(Desaminotyrsoyl tyrosinemethylparaben ester-glutarate), and DTPP P(Desaminotyrsoyl tyrosinepropylparaben ester-glutarate).

In some embodiments, the polymer is one more polymers from the DTE-DTsuccinate family of polymers, e.g., the P22-xx family of polymers havingfrom 0-50%, 5-50%, 5-40%, 1-30% or 10-30% DT, including but not limitedto, about 1, 2, 5, 10, 15, 20, 25, 27.5, 30, 35, 40%, 45% and 50% DT. Insome embodiments, the polymer is P22-27.5 DT.

In some embodiments, the polymer has diphenol monomer units that arecopolymerized with an appropriate chemical moiety to form a polyarylate,a polycarbonate, a polyiminocarbonate, a polyphosphonate or any otherpolymer.

In some embodiments, the polymer is tyrosine-based polyarylate. In someembodiments, the polymer includes blends and copolymers withpolyalkylene oxides, including polyethylene glycol (PEG).

In some embodiments, the polymer can have from 0.1-99.9% PEG diacid topromote the degradation process. In some embodiments, the polymerincludes blends of polyarylates or other biodegradable polymers withpolyarylates.

The polymer is configured to release the HA and/or the API over time, asdiscussed herein. In some embodiments, the polymer is configured torelease the HA and/or the API over a time period ranging from about 1hour to about 168 hours. In some embodiments, the polymer is configuredto release the HA and/or the API over a time period ranging from 1 hourto 72 hours. In some embodiments, the polymer is configured to releasethe HA and/or the API over a time period ranging from 1 hour to 24hours.

In some embodiments, the polymer is configured to release the HA and/orthe API over time in an area surrounding or adjacent to anchorage device20 (such as, for example, within the device “pocket” or within 3 inchesin all dimensions). In some embodiments, the polymer is configured torelease the HA and/or the API for up to 30 hours. In some embodiments,the polymer is configured to release between about 40% and about 100% ofthe HA and/or the API over a period of at least about 30 hours. In someembodiments, the polymer is configured to release 60% and about 100% ofthe HA and/or the API over a period of at least about 30 hours. In someembodiments, the polymer is configured to release between about 65% andabout 100% of the HA and/or the API over a period of at least about 36hours. In some embodiments, the polymer is configured to release 80% andabout 100% of the HA and/or the API over a period of at least about 36hours. In some embodiments, the polymer is configured to release betweenabout 60% and about 100% of the HA and/or the API over a period of atleast about 48 hours. In some embodiments, the polymer is configured torelease 80% and about 100% of the HA and/or the API over a period of atleast about 48 hours. In some embodiments, the polymer is configured torelease between about 60% and about 100% of the HA and/or the API over aperiod of at least about 60 hours. In some embodiments, the polymer isconfigured to release 80% and about 100% of the HA and/or the API over aperiod of at least about 60 hours. In some embodiments, the polymer isconfigured to release 80% and about 100% of the HA and/or the API within48 hours. In some embodiments, the polymer is configured to release 80%and about 100% of the HA and/or the API within 24 hours.

In some embodiments, the polymer is configured to release no more than60% of the HA and/or the API within 24 hours. In some embodiments, thepolymer is configured to release no more than 90% of the HA and/or theAPI after 60 hours. In some embodiments, the polymer is configured torelease no more than 50% of the HA and/or the API within 12 hours. Insome embodiments, the polymer is configured to release between about 40%and about 90% of the HA and/or the API between 12 and 24 hours. In someembodiments, the polymer is configured to release between about 60% andabout 100% of the HA and/or the API between 24 and 36 hours. In someembodiments, the polymer is configured to release between about 65% andabout 100% of the HA and/or the API between 36 and 48 hours. In someembodiments, the polymer is configured to release between about 70% andabout 100% of the HA and/or the API between 48 and 60 hours.

Substrate 22 may be coated with single or multiple coating layers ofcoating 24, depending on, for example, the amount of the HA and/or theAPI to be delivered and desired release rate. Each layer of coating 24may contain the same or different amounts of the HA and/or the API. Forexample, a first layer of coating 24 may contain the HA and/or the API,while the second layer of coating 24 contains either no HA or API or alower concentration of the HA and/or the API. As another example, afirst layer of coating 24 may comprise the HA and/or the API in a firstpolymer, while the second layer of coating 24 comprises the HA and/orthe API in a second polymer that is different than the first polymer.

In some embodiments, shown in FIGS. 3 and 4, substrate 22 is a pocket orenvelope in which medical device 25 can be at least partially disposed.That is, substrate 22 is a pouch, bag, covering, shell, or receptacle.For example, substrate 22 can include a first piece 22 a and a secondpiece 22 b that is joined with first piece 22 a. First and second pieces22 a, 22 b are joined to form the pocket or envelope. In someembodiments, first and second pieces 22 a, 22 b are joined along threesides of the pocket or envelope to form a cavity C. First and secondpieces 22 a, 22 b are not joined at a fourth side of the pocket orenvelope to define opening O such that medical device 25 can be insertedthrough opening O and into cavity C to enclose, encase or surround allor a portion of medical device 25 within cavity C. In some embodiments,first and second pieces 22 a, 22 b are joined with one another alongthree sides of the pocket or envelope by heat, ultrasonically, bonding,knitting, or adhesive. In some embodiment, the pocket or envelope ismonolithically formed by molding the pocket or envelope or producing thepocket or envelope by 3D printing, for example. In some embodiments,anchorage device 20 is pre-formed to provide cavity C with a selectedsize and shape. In some embodiments, the selected size and shape ofcavity conforms to the size and shape of medical device 25. In someembodiments, the selected size and shape of cavity conforms to the sizeand shape of medical device 25 and the size and shape of an insert of apackage, as discussed herein. That is, the insert and medical device 25have the same size and shape so that the insert can be inserted intocavity C while anchorage device 20 is packaged and medical device 25 canbe inserted into cavity C when anchorage device 20 is unpackaged, asdiscussed herein. In some embodiments, opening O is configured to have aselected size and shape that allows the insert and medical device 25 tobe inserted through opening O and into cavity C. In some embodiments,substrate 22 is made from a material or includes a reinforcing material(e.g., stitching) or other structure around opening O that allowsopening O to maintain the selected size and shape of opening O. That is,opening O will not collapse without any structure between pieces 22 a,22 b or any force that spaces piece 22 a away from piece 22 b. Thisallows opening O to maintain the selected size and shape when the insertor medical device 25 is not positioned in cavity C or opening O. In someembodiments, substrate 22 is made from a material that causes opening Oto collapse from the selected size and shape of opening O to a size andshape that is smaller than the selected size and shape of opening O.That is, opening O will collapse without any structure between pieces 22a, 22 b or a force that spaces piece 22 a away from piece 22 b. As such,opening O will collapse when the insert or medical device 25 are notpositioned in cavity C or opening O.

In some embodiments, first and second pieces 22 a, 22 b are portions ofa single sheet that is bent to produce a fold at one end of the pocketor envelope. First and second pieces 22 a, 22 b are joined along sidesof the pocket or envelope that extend transverse to the fold such thatthe fold and the sides of the pocket or envelope do not have anyopenings. First and second pieces 22 a, 22 b are not joined at an end ofthe pocket or envelope opposite the fold to define an opening at the endsuch that medical device 25 can be inserted through the opening and intoa cavity defined by inner surfaces of first and second pieces 22 a, 22b.

In some embodiments, first and second pieces 22 a, 22 b each include amesh. In some embodiments, first piece 22 a includes a mesh includingpores having a first size and second piece 22 b includes a meshincluding pores having a second size, wherein the first size isdifferent than the first size. In some embodiments, the first size isgreater than the second size. In some embodiments, the first size isless than the second size. In some embodiments, first and second pieces22 a, 22 b each include a thin walled structure that does not have anypores or apertures. In some embodiments one of first and second pieces22 a, 22 b includes a mesh and the other one of first and second pieces22 a, 22 b includes a thin walled structure that does not have any poresor apertures.

In some embodiments, first and second pieces 22 a, 22 b are formed fromthe same material. In some embodiments one of first and second pieces 22a, 22 b is formed from a first material, such as, for example, one ormore of the materials discussed herein, and the other one of first andsecond pieces 22 a, 22 b is made from a second material, such as, forexample, one or more of the materials discussed herein, wherein thesecond material is different than the first material. For example, firstpiece 22 a may be formed from a biodegradable and/or bioresorbablematerial and second piece 22 b may be formed from a non-biodegradableand/or non-bioresorbable material, or vice versa. In some embodiments,first and second pieces 22 a, 22 b are each formed from a biodegradableand/or bioresorbable material, wherein the biodegradable and/orbioresorbable materials degrade and/or resorb at the same rate. In someembodiments, first and second pieces 22 a, 22 b are formed fromdifferent biodegradable and/or bioresorbable materials, wherein one ofthe biodegradable and/or bioresorbable materials degrades and/or resorbsmore quickly than the other biodegradable and/or bioresorbable material.

In some embodiments, first and second pieces 22 a, 22 b each include asingle layer of material, such as, for example, one or more of thematerials discussed herein. In some embodiments, at least one of firstand second pieces 22 a, 22 b includes multiple layers. In someembodiments, the multiple layers include more than one layer of a mesh.In some embodiments, the multiple layers include more than one layer ofa thin walled structure that does not have any pores or apertures. Insome embodiments, the multiple layers include one or more layer of amesh and one or more layer of a thin walled structure that does not haveany pores or apertures. In some embodiments, the multiple layers includeone or more layer of a mesh and one or more layer of a thin walledstructure, wherein one of the layers of mesh is positioned between twolayers of the thin walled structure. In some embodiments, the multiplelayers include one or more layer of a mesh and one or more layer of athin walled structure that does not have any pores or apertures, whereinone of the layers of thin walled structure is positioned between twolayers of the mesh.

In embodiments discussed herein wherein anchorage device 20 is a pocketor envelope, a first coating 24 can be applied to first piece 22 a and asecond coating 24 can be applied to second piece 22 b. In someembodiments, the first and second coatings 24 are different. In someembodiments, the first and second coatings 24 release the HA and/or theAPI at different rates and/or over different lengths of time. In someembodiments, the first coating 24 includes a first amount of the HAand/or the API and the second coating 24 includes a second amount of theHA and/or the API, the first amount being different than the secondamount. In some embodiments, the first and second coatings 24 are thesame.

In some embodiments, anchorage device 20 includes a hydrophiliccomponent, such as, for example, PEG and a crosslinking agent that isapplied to substrate 22. The hydrophilic component and the crosslinkingagent form a hydrogel that absorbs blood and reduces bleeding when incontact with blood or tissue fluid. In some embodiments, the hydrophiliccomponent and the crosslinking agent are sprayed directly onto substrate22. In some embodiments, the hydrophilic component and the crosslinkingagent are provided in a polymer, such as, for example, one or more ofthe polymers discussed herein, and the polymer is applied directly ontosubstrate 22. In some embodiments, the hydrophilic component and thecrosslinking agent are provided in a patch, such as, for example, theVeriset™ hemostatic patch available from Medtronic, Inc., and the patchis applied directly onto substrate 22. In some embodiments, the patchcomprises a plurality of layers. For example, a first layer of the patchcan include a hemostatic agent, such as, for example, oxidizedregenerated cellulose and/or one or more of the hemostatic agentsdiscussed herein. A second layer of the patch can include a crosslinkingagent, such as, for example, trilysine and/or one or more of thecrosslinking agents discussed herein. A third layer of the patch caninclude a hydrophilic agent, such as, for example, PEG and/or one ormore of the hydrophilic agents discussed herein. The second layer of thepatch is positioned between the first and third layers of the patch.

In some embodiments, the hydrophilic component comprises thermogellinghydrogels, PEG-PLGA copolymers, PEG-Poly(N-isopropyl acrylamide),Pluronic (PEO-PPO-PEO triblock), PEG-PCL polymers, PEG-based amphiphiliccopolymers modified by anionic weak polyelectrolytes, (such aspolyacrylic acid, polyglutamic acid) and polymers containing sulfonamidegroups), PEG-based amphiphilic copolymers modified by cationic weakpolyelectrolytes (such as poly (2-vinyl pyridine), Poly(beta-aminoesters), poly (2-(dimethylamino)ethyl methacrylate), multiarm PEGderivatives such as those available from JenKem technology, multiarmedblock and graft PLA copolymers with PEG, PEG with stereo complexedpoly(lactide), acrylated polymers (such as Polyvinylalcohol, dextran,Polyvinylpyrollidone, chitosan, alginate, hyaluronic acid), andcombinations thereof. In some embodiments, the crosslinking agentcomprises one or more agents that induce polymerization of vinyl groupsusing various initiators, light or redox reactions, or by reactions suchas Schiff base formation, Michael type additions, peptide ligation,clock chemistry of functional groups present; one or more agents thatinduce crosslinking by enzymatic reaction (transglutaminase mediatedreaction between carboxamide and amine on proteins),stereo-complexation, metal chelation (alginates using calciumCaI2),thermogelation, self-assembly (formation of super helices from proteinchains) inclusion complexation (using cyclodextrin); and combinationsthereof.

In some embodiments, an anchorage device, such as, for example,anchorage device 20 and a medical device, such as, for example, medicaldevice 25 are implanted into a body of a patient. The anchorage devicereleases a hemostatic agent or active pharmaceutical ingredient, suchas, for example, the HA and/or the API, to reduce or prevent bleedingwithin the patient or treat one of the conditions as discussed herein.In some embodiments, anchorage device 20 is implanted within the patientwithout medical device 25 and medical device 25 is coupled to orinserted into anchorage device 20 after anchorage device 20 isimplanted. In some embodiments, medical device 25 is coupled to orinserted into anchorage device 20 before anchorage device 20 isimplanted within the patient and anchorage device 20 and medical device25 are implanted within the patient together.

In some embodiments, medical device 25 is removed from the patient afterthe treatment is completed. In some embodiments, anchorage device 20remains implanted within the patient after medical device 25 is removed.In some embodiments, anchorage device 20 is removed from the patientafter medical device 25 is removed. To remove anchorage device 20,tissue that is ingrown within substrate 22 of anchorage device 22 can becut or otherwise detached from substrate 22. In some embodiments, aportion of anchorage device 20 may not be removable from the tissue andwill remain implanted within the patient.

In some embodiments, the method includes making a customized anchoragedevice, wherein a hemostatic agent and/or active pharmaceuticalingredient is selectively applied to the anchorage device to positionthe hemostatic agent or active pharmaceutical ingredient such that thehemostatic agent is targeted to a location of blood loss in a patientwhen the anchorage device is implanted within the patient or such thatactive pharmaceutical ingredient is targeted to a location to treat atleast one condition when the anchorage device is implanted within thepatient. As such, the method includes identifying a location within thepatient that has a certain condition, such as, for example, infection,scarring and/or infection, or a location where blood lose is occurringor is likely to occur. The medical practitioner than may select aportion or portions of the substrate to which hemostatic agent and/oractive pharmaceutical ingredient should be applied so that thehemostatic agent or active pharmaceutical ingredient is positioned at oradjacent to the location within the patient when the anchorage device isimplanted within the patient. In some embodiments, the method furtherincludes applying the hemostatic agent and/or active pharmaceuticalingredient to the substrate at the selected portion or portions of thesubstrate. For example, in one embodiment, the method includes loadingdata into a computer regarding the selected portion or portions of thesubstrate and using a 3D printer that is connected to the computer toprint the hemostatic agent and/or active pharmaceutical ingredient ontothe selected portion or portions of the substrate. It is envisioned thatthe medical practitioner may also select the amount of the hemostaticagent and/or active pharmaceutical ingredient that is applied to theportion or portions of the substrate. For example, the medicalpractitioner can choose to apply more of the hemostatic agent and/oractive pharmaceutical ingredient to one portion of the substrate thananother portion of the substrate. This information can be input into thecomputer such that the 3D printer prints the selected amounts of thehemostatic agent and/or active pharmaceutical ingredient on the portionor portions of the substrate. In some embodiments, the medicalpractitioner may choose to apply more of the hemostatic agent and/oractive pharmaceutical ingredient on one portion of the substrate thananother portion of the substrate or the same amount of the hemostaticagent and/or active pharmaceutical ingredient on each portion of thesubstrate. It is envisioned that the anchorage device with thehemostatic agent and/or active pharmaceutical ingredient applied to theselected portion or portions of the substrate in the selected amountscan be made in a manufacturing facility, in a hospital, or in anoperating room. In some embodiments, the process of making the anchoragedevice may include starting with a blank substrate and then applying thehemostatic agent and/or active pharmaceutical ingredient to the blanksubstrate in the manner discussed above. In some embodiments, theprocess of making the anchorage device includes forming the substrateand applying the hemostatic agent and/or active pharmaceuticalingredient to the substrate. In some embodiments, the process of makingthe anchorage device includes forming the substrate with the hemostaticagent and/or active pharmaceutical ingredient applied to the substratesimultaneously. For example, a medical practitioner can input into acomputer the type of substrate desired (size, shape, material, etc.) theportions of the substrate that should include the hemostatic agentand/or active pharmaceutical ingredient, and the amounts of thehemostatic agent and/or active pharmaceutical ingredient to be includedin each of the portions. A 3D printer that is connected to the computercan then print the substrate with the hemostatic agent and/or activepharmaceutical ingredient on the substrate at the selected portions andin the selected amounts.

In some embodiments, system 15 include a package 44, shown in FIGS.9-11, configured to house anchorage device 20 as anchorage device 20 isbeing transported from a manufacturer to a user, such as, for example, amedical practitioner. Package 44 includes a body 46 having a side wall48. Wall 48 includes a top end 50 and an opposite bottom end 52. Body 46comprises a bottom wall 54 coupled to end 52. An inner surface 56 ofwall 56 and an inner surface 58 of wall 54 define a cavity 60. End 50defines an opening 62 that is in communication with cavity 60. In someembodiments, body 46 includes a flange 64 extending outwardly from end50. Opening 62 extends through flange 64. In some embodiments, all or aportion of body 46 is opaque to prevent light from moving through wall48 and/or wall 54 to maintain sterility within cavity 60. In someembodiments, all or a portion of body 46 is transparent to allow medicaldevice 25 to be viewed through wall 48 and/or wall 54 when medicaldevice 25 is positioned within cavity 60.

In some embodiments, materials for vacuum thermal forming includeAcrylonitrile butadiene styrene (ABS), Polychlorotrifluoroethylene(PCTFE), polyvinyl chloride (PVC), Polyvinylidene chloride (PVDC),Cyclic olefin copolymers (COC) or polymers (COP). Packaging finalthickness may range from 0.005″ to 0.020″ or so depending on stiffnessof the chosen plastic and necessary moisture blocking. The materials maybe blow molded or cold formed. However, vacuum thermal forming is likelythe most economical.

Package 44 further includes an insert 66 extending from wall 54 suchthat insert 66 is positioned in cavity 60. Insert 66 has a size andshape defined by a first side wall 68 and an opposite second side wall70. Walls 68, 70 each extend from a top wall 72 of insert 66 to anopposite bottom wall 74 of insert 66. In some embodiments, the wall 72is convexly curved from wall 68 to wall 70. In some embodiments, thewall 68 extends parallel to wall 70 from wall 72 to wall 74. In someembodiments, insert 66 includes a front wall 76 and an opposite backwall 78 that each extend from wall 72 to wall 74 and from wall 68 towall 70. In some embodiments, wall 76 extends parallel to wall 78 fromwall 72 to wall 74.

In embodiments wherein anchorage device 20 is an envelope, as discussedherein, anchorage device can be inserted into package 44 by insertinganchorage device 20 into cavity 60 such that that insert 66 ispositioned within cavity C. That is, anchorage device 20 is movedrelative to package 44 such that insert 66 moves through opening O andinto cavity C. In some embodiments, insert 66 forms a close fit withanchorage device 20 such that an inner surface of anchorage device thatdefines cavity C directly engages an outer surface of insert 66. In someembodiments, the outer surface of insert 66 is smooth and/or even toprevent tearing or otherwise damaging anchorage device 20. In someembodiments, the outer surface of insert 66 is rough and/or textured tofacilitate gripping of insert 66 with anchorage device 20. In someembodiments, package 44 includes a lid, such as, for example, a cover 80that is attached to flange 64 such that cover 80 completely coversopening 62, as shown in FIG. 11. In some embodiments, cover 80 iscoupled to flange 64 via adhesive. In some embodiments, cover 80 issealed or bonded to flange 64 using heat sealing. In some embodiments,cover 80 cannot be removed from body 46 without damaging and/or breakingcover 80 to prevent cover 80 from being reattached to body 46.

In some embodiments, all or a portion of package 44 is made frompolyethylene terephythalate (PET). In some embodiments, package 44comprises one or more layers having an oxygen barrier material. In someembodiments, the oxygen barrier material is present in the container inan amount between about 0.5 wt. % and about 5.0 wt. % of the container.In some embodiments, the oxygen barrier material is present in thecontainer in an amount about 2.0 wt. % of the container. In someembodiments, the oxygen barrier is a passive barrier and is unreactivewith oxygen. In some embodiments, the oxygen barrier is an oxygenscavenger and is reactive with oxygen to capture the oxygen. In someembodiments, the oxygen scavenger includes one or more oxygen barrier,such as, for example, one or more polymers, metals, compatibilizers,catalysts, and/or fatty acid salts.

In some embodiments, system 15 includes a powder that includes one ormore of the HAs and one or more of the APIs, as discussed herein. Inparticular, the one or more HAs are included in a first powder 82 andthe one or more APIs are included in a second powder 84. First andsecond powders 82, 84 are combined to create a third powder 86, as shownin FIG. 12. In some embodiments, the ratios of powder can range from 9:1through 1:9, with the preferred ratio about 1:1.

Powder 86 is configured to be delivered to a surgical site via adelivery device, such as, for example, a syringe 88. In someembodiments, powder 82 is obtained by grinding an anchorage device, suchas, for example, anchorage device 20 into a powder. That is, anchoragedevice 20 is ground into powder 82 such that powder 82 includes all ofthe components of anchorage device 20, including, for example, substrate22 and coating 24. In some embodiments, powder 84 is obtained bygrinding a material that includes a hemostatic agent. In someembodiments, the material is a VERISET hemostat 90 that is configured tobe applied as a patch to control bleeding and is made from oxidizedcellulose and a PEG compound. That is, hemostat 90 is ground into powder84 such that powder 84 includes all of the components of hemostat 90. Insome embodiments, powders 82, 84 are admixed to make powder 86. In someembodiments, powder 82 is made using a spray drying process, as shown inFIG. 16. In particular, hot air 92 acts on a slurry 94 to form particles96 that are collected as powder 82. In some embodiments, 94 can be aslurry is made of powder 86 by mixing it with selected solvent orsolvent system (THF and methanol). Powder 82 can be made from 94, whichis a solution of coating polymer and drugs from device 20.

In some embodiments, powder 86 is administered to a surgical site toprovide treatment to the surgical site via syringe 88. In someembodiments, the surgical site includes areas adjacent to theimplantation of a neurostimulator, as shown in FIG. 19. In someembodiments, the surgical site includes areas adjacent to theimplantation of a spinal construct, as shown in FIG. 20. In someembodiments, the surgical site includes areas adjacent to theimplantation of a pacemaker, as shown in FIG. 21. In some embodiments,powder 86 is administered to the surgical site is the only treatmentprovided to the surgical site. In some embodiments, powder 86 isadministered to the surgical site before an anchorage device, such as,for example, anchorage device 20, is coupled to a medical device presentat the surgical site, such as, for example, medical device 25. In someembodiments, powder 86 is administered to the surgical site after ananchorage device, such as, for example, anchorage device 20, is coupledto a medical device present at the surgical site, such as, for example,medical device 25. In some embodiments, powder 86 is administered to thesurgical site before and after an anchorage device, such as, forexample, anchorage device 20, is coupled to a medical device present atthe surgical site, such as, for example, medical device 25.

In some embodiments, kits are provided that include one or a pluralityof anchorage devices, such as, for example, anchorage devices 20. It iscontemplated that each of the anchorage devices included can have adifferent configuration. In some embodiments, the anchorage devices caninclude different coatings 24. In some embodiments, the anchoragedevices can include different sizes. In some embodiments, the anchoragedevices can include different shapes. In some embodiments, the anchoragedevices can include different anchorage devices that are designed foruse with different medical devices, such as, for example, theimplantable or non-implantable medical devices discussed herein. In someembodiments, the kits include one or a plurality of medical devices,such as, for example, the implantable or non-implantable medical devicesdiscussed herein. In some embodiments, the kit includes instructions foruse. In some embodiments, the kit can include one or a plurality ofpowders that can be used to treat a surgical site, such as, for example,one or more powders that are the same or similar to powder 86. In someembodiments, the kit includes items that are used to make the anchoragedevices, such as, for example, the materials used to make the substrate,the hemostatic agent(s), the active pharmaceutical ingredient(s), acomputer with a processor capable of receiving data and communicatingwith a 3D printer to create an anchorage device having the parametersthat were input into the computer (e.g., size, shape, material,agents/ingredients on selected areas of the substrate in selectedamounts) and a 3D printer capable of making the anchorage device basedupon data that is input into the computer regarding the parameters ofthe implant.

It will be understood that various modifications may be made to theembodiments disclosed herein. Therefore, the above description shouldnot be construed as limiting, but merely as exemplification of thevarious embodiments. Those skilled in the art will envision othermodifications within the scope and spirit of the claims appended hereto.

What is claimed is:
 1. A surgical system comprising: an implantablemedical device having a size and shape; a surgical device comprising asubstrate and a coating that covers at least a portion of the substrate,the coating comprising collagen, glycerin and a hemostatic agent, thesubstrate comprising a first piece and a second piece that is joinedwith the first piece, the first piece and the second piece forming apocket having a cavity and an opening that is in communication with thecavity, the device being pre-formed such that a size and shape of thecavity conforms to the size and shape of the implantable medical device.2. The surgical system recited in claim 1, wherein the implantablemedical device is configured to be inserted through the opening and intothe cavity.
 3. The surgical system recited in claim 1, wherein theimplantable medical device is a pacemaker.
 4. The surgical systemrecited in claim 1, wherein the implantable medical device is acardioverter-defibrillator.
 5. The surgical system recited in claim 1,wherein the implantable medical device is positioned in the cavity. 6.The surgical system recited in claim 5, wherein the implantable medicaldevice is a pacemaker.
 7. The surgical system recited in claim 5,wherein the implantable medical device is a cardioverter-defibrillator.8. The surgical system recited in claim 1, wherein the hemostatic agentis trans-4-(aminomethyl)cyclohexanecarboxylic acid (C₈H₁₅NO₂).
 9. Thesurgical system recited in claim 1, wherein the coating consists ofcollagen, glycerin and the hemostatic agent.
 10. The surgical systemrecited in claim 1, wherein the collagen is CPP collagen.
 11. Thesurgical system recited in claim 1, wherein the collagen is CPXcollagen.
 12. The surgical system recited in claim 1, wherein thecoating is free of ECM collagen.
 13. The surgical system recited inclaim 1, further comprising a package, the package including an apertureand an insert positioned within the aperture, the insert beingconfigured to be positioned in the cavity to maintain the size and shapeof the cavity.
 14. The surgical system recited in claim 1, furthercomprising a package, the package including an aperture and an insertpositioned within the aperture, the insert being positioned in thecavity to maintain the size and shape of the cavity.
 15. A surgicalsystem comprising: a package, the package including an aperture and aninsert positioned within the aperture; an implantable medical devicehaving a size and shape, wherein the implantable medical device is apacemaker or a cardioverter-defibrillator; a surgical device comprisinga substrate and a coating that covers at least a portion of thesubstrate, the coating comprising collagen, glycerin and a hemostaticagent, the collagen including CPP collagen or CPX collagen, thesubstrate comprising a first piece and a second piece that is joinedwith the first piece, the first piece and the second piece forming apocket having a cavity and an opening that is in communication with thecavity, the device being pre-formed such that a size and shape of thecavity conforms to the size and shape of the implantable medical device,the insert being positioned in the cavity to maintain the size and shapeof the cavity.
 16. The surgical system recited in claim 15, wherein thehemostatic agent is trans-4-(aminomethyl)cyclohexanecarboxylic acid(C₈H₁₅NO₂).
 17. The surgical system recited in claim 16, wherein thecoating consists of collagen, glycerin and the hemostatic agent.
 18. Asurgical system comprising: a package, the package including an apertureand an insert positioned within the aperture; an implantable medicaldevice having a size and shape, wherein the implantable medical deviceis a pacemaker or a cardioverter-defibrillator; a surgical devicecomprising a substrate and a coating that covers at least a portion ofthe substrate, the coating comprising collagen, glycerin and ahemostatic agent, the collagen including CPP collagen or CPX collagen,the substrate comprising a first piece and a second piece that is joinedwith the first piece, the first piece and the second piece forming apocket having a cavity and an opening that is in communication with thecavity, the device being pre-formed such that a size and shape of thecavity conforms to the size and shape of the implantable medical device,the implantable medical device being positioned in the cavity, theinsert being configured to be positioned in the cavity to maintain thesize and shape of the cavity.
 19. The surgical system recited in claim18, wherein the hemostatic agent istrans-4-(aminomethyl)cyclohexanecarboxylic acid (C₈H₁₅NO₂).
 20. Thesurgical system recited in claim 19, wherein the coating consists ofcollagen, glycerin and the hemostatic agent.